| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 07.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 11.07.00 |
| PATENT TITLE |
Use of neuregulins as modulators of cellular communication |
| PATENT ABSTRACT |
The present invention relates to methods of affecting cellular communication in a vertebrate. The communication is affected by the administration of a neuregulin to a vertebrate, where the neuregulin interacts with a first cell type which results in the production of a product (i.e., Product A). This product, in turn, affects the function of a second cell type. Methods are disclosed in which the affect in function of the second cell type, described above, results in the production of a second product (i.e., Product B) which, in turn, can affect the function of the first cell type or a third cell type. Additional methods are included for treatment of disorders involving an altered or inadequate level of production of a product involved in cellular communication. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 17.11.94 |
| PATENT REFERENCES CITED |
Peles et al. (1993) Bioessays 15, 815-824. Danilenko et al. (1994) FASEB Journal 8 (4-5), A535. Brockes, J.P. et al., Development in the Nervous System, 309-327, 1980, The neuron as a Source of Mitogen: Its Influence on the Proliferation of Glial and Non-neural Cells. Danilenko et al., FASEB Journal, vol. 8 Numbers 4-5, A535, 1994, Neu Differentiation Factor (NDEF) Accelerates Epidermal Migration and Differentiation in Excisional Wounds. Marshall, Special News Report, vol. 269, 1050-1055, Aug. 25, 1995, Gene Therapy's Growing Pains. Verdi, et al, Neuron, vol. 16, 515-527, Mar. 1996, A Reciprocal Cell-Cell Interation Mediated by NT-3 and Neuregulins Controls the Early Survival and Development of Sympathetic Neuroblasts. Yao et al, Proc. Natl. Acad. Sci. USA, vol. 89, 3357-3361, Apr. 1992, Expression of Human Factor IX in Mice after Injection of Genetically Modified Myoblasts. Cheema, et al, Journal of Neuroscience Research, vol. 37, 213-218, 1994, Leukemia Inhibitory Factor Prevents the Death of Axotomised Sensory Neurons in the Dorsal Root Ganglia of the Neonatal Rat. Curtis, et al, Neuron, vol. 12, 191-204, 1994, Retrograde Axonal Transport of LIF is Increased by Peripheral Nerve Injury: Correlation with Increased LIF Expression in Distal Nerve. Fann, et al, Journal of Neurochemistry, vol. 61, 1349-1355, 1993, A Novel Approach to Screen for Cytokine Effects on Neuronal Gene Expression. Grinspan, et al, The Journal of Neuroscience, vol. 16, 6107-6118, Axonal Interactions Regulate Schwann Cell Apoptosis in Developing Peripheral Nerve: Neuregulin Receptors and the Role of Neuregulins. Hefti, Journal of Neurobiology, vol. 25, No. 11, 1418-1435, 1994, Neurotrophic Factor Therapy for Nervous System Degenerative Diseases. Henderson, et al, Science, vol. 266, 1062-1064, 1994, GDNF: A Potent Survival Factor for Motoneurons Present in Peripheral Nerve and Muscle. Hughes, et al, Journal of Neuroscience Research, vol. 36, 663-671, 1993, Members of Several Gene Families Influence Survival of Rat Motoneurons in Vitro and In Vivo. Kotzbauer, et al, Neuron, vol. 12, 763-773, 1994, Postnatal Development of Survival Responsiveness in Rat Sympathetic Neurons to Leukemia Inhibitory Factor and Ciliary Neurotrophic Factor. Lin, et al, Science, vol. 260, 1130-1132, 1993, GDNF: A Glial Cell Line-Derived Neurotrophic Factor for Midbrain Dpaminergic Neurons. Mahanthappa, et al, The Journal of Neuroscience, vol. 16, 4673-4683, 1996, Glial Growth Factor 2, a Soluble Neuregulin, Directly Increases Schwann Cell Motility and Indirectly Promotes Neurite Outgrowth. Martinou, et al, Neuron, vol. 8, 737-744, 1992, Cholinergic Differentiation Factor (CDF/LIF) Promotes Survival of Isolated Rat Embryonic Motoneurons in Vitro. Oppenheim, et al., Nature, vol. 373, 344-346, 1995, Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Pinkas-Kramarski, Proc. Natl. Acad. Sci. USA, vol. 91, 9387-9391, 1994, Brain neurons and glial cells express Neu differentiation factor/heregulin: A survival factor for astrocytes. Qin-Wei, et al, The Journal of Neuroscience, vol. 14, 7629-7640, 1994, Cell Death of Spinal Motoneurons in the Chick Embryo following Deafferentation: Rescue Effects of Tissue Extracts, Soluble Proteins, and Neurotrophic Agents. Syroid, et al, Proc. Natl. Acad. Sci. USA, vol. 93, 9229-9234, 1996, Cell Death in the Schwann Cell Lineage and its Regulation by Neuregulin. Trachtenberg, et al, Nature, vol. 379, 174-176, 1996, Schwann Cell Apoptosis at Developing Neuromuscular Junctions is Regulated by Glial Growth Factor. Xie, et al, Biotechniques, vol. 11, No. 3, 325-327, 1991, Rapid, Small-Scale RNA Isolation from Tissue Culture Cells. Yamamori, et al, Science, vol. 246, 1412-1416, 1989, The Cholinergic Neuronal Differentiation Factor from Heart Cells is Identical to Leukemia Inhibitory Factor. Yan, et al, Nature, vol. 373, 341-344, 1995, In Vivo Neurotrophic Effects of GDNF on Neonatal and Adult Facial Motor Neurons. Yuen, et al., Annals of Neurology, vol. 40, No. 3, 340-354, 1996, Therapeutic Potential of Neurotrophic Factors for Neurological Disorders. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A method of affecting cellular communication between neuronal-associated cells and neuronal cells in a vertebrate, comprising administration of a neuregulin with p185.sup.erbB2, p185.sup.erbB3 or p185.sup.erbB4 binding activity to said vertebrate wherein said neuregulin interacts with said neuronal-associated cells, resulting in production of at least one neurotrophic agent by said neuronal-associated cells and said neurotrophic agent or agents affect the mitotic activity, survival, differentiation or neurite outgrowth of said neuronal cells. 2. A method of claim 1 wherein said vertebrate is a human. 3. A method of claim 1 wherein said neuronal-associated cells are nervous system support cells. 4. A method of claim 3 wherein said nervous system support cells are glial cells. 5. A method of claim 1 wherein said neuronal-associated cells are sensory organ cells. 6. A method of claim 1 wherein said neuronal-associated cells are muscle cells. 7. A method of claim 1 wherein said neuronal cells are cholinergic neurons. 8. A method of claim 1 wherein said neuronal cells are non-cholinergic neurons. 9. A method of claim 1 wherein said neuregulin is rhGGF2. 10. A method of affecting cellular communication between neuronal-associated cells and neuronal cells in the peripheral nervous system of a vertebrate, comprising administration of a neuregulin with p185.sup.erbB2, p185.sup.erbB3 or p185.sup.erbB4 binding activity to said vertebrate wherein said neuregulin interacts with said neuronal-associated cells, resulting in production of at least one neurotrophic agent by said neuronal-associated cells and said neurotrophic agent or agents affect the mitotic activity, survival, differentiation or neurite outgrowth of said neuronal cells. 11. A method of claim 10 wherein said neuronal associated cells are Schwann cells. 12. A method of claim 10 wherein said neuronal-associated cells are muscle cells. 13. A method of claim 10 wherein said neuronal-associated cells are skeletal muscle cells. 14. A method of claim 10 wherein said neuronal-associated cells are cardiac muscle cells. 15. A method of claim 10 wherein said neuronal-associated cells are smooth muscle cells. 16. A method of claim 10 wherein said neuronal-associated cells are sensory organ cells. 17. A method of claim 10 wherein said neuronal cells are cholinergic neurons. 18. A method of claim 10 wherein said neuronal cells are non-cholinergic neurons. 19. A method of treating a neurological disorder involving neuronal degeneration in the peripheral nervous system of a mammal, comprising administration of a therapeutically effective amount of a neuregulin with p185.sup.erbB2, p185.sup.erbB3 or p185.sup.erbB4 binding activity to said mammal wherein said neuregulin interacts with neuronal-associated cells, resulting in the production of at least one neurotrophic agent which affects the mitotic activity, survival, differentiation or neurite outgrowth of neuronal cells. 20. A method of treating peripheral neuropathy and peripheral nerve injury comprising administration of a therapeutically effective amount of a neuregulin with p185.sup.erbB2, p185.sup.erbB3 or p185.sup.erbB4 binding activity wherein said neuregulin interacts with a neuronal-associated cells, resulting in production of at least one neurotrophic agent by said neuronal-associated cells and said neurotrophic agent or agents affect the mitotic activity, survival, differentiation or neurite outgrowth of neuronal cells. |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION This invention relates to methods of affecting cellular communication. BACKGROUND OF THE INVENTION Vertebrate cells depend on externally produced factors for growth, differentiation and survival. These factors can be in the form of diffusible, molecules that act at a distance from their site of synthesis. Alternatively these factors can be in the form of cell-surface-bound molecules that rely on cell-to-cell contact for their function. In many cases, different cell types may interact in a reciprocal manner in that both cell types produce factors that affect the other cell type. Vertebrates rely on these reciprocal interactions during embryogenesis and during the response to injury and disease. Interdependence of cells and tissues plays important roles in the vertebrate nervous system. The nervous system is composed of neurons and neuroglial support cells. Peripheral nervous system axons are ensheathed by neuroglial cells (Schwann cells) and target organs which include skin, sensory receptors, muscle and other neurons. Additionally, peripheral axons interact with components of the central nervous system in the spinal cord. These include neurons and neuroglial cells such as astrocytes and oligodendrocytes . It is well established that neurons and the tissues and cells with which they interact are dependent on each other for trophic support. This relationship is mediated by factors (proteins) produced by neurons that maintain the viability of target tissues (e.g. motor neuron derived factors that maintain muscle integrity) and neurotrophic factors produced by target (and other) tissues that maintain neuronal viability (e.g. muscle derived factors that maintain motor neuron viability). This interdependence plays an important role in embryonic development, maintenance of viability and response to injury in the nervous system and its targets. The survival of various neuronal populations has been thought to be dependent only upon neurotrophic factors produced by targets of innervation. Recently it has been realized that neurotrophic factors are also derived from axonally associated cells (periaxonal glia), soma associated (perisomatic) cells (e.g. glia and efferent synapses) and from autocrine sources. These proteins are taken up by neurons where they exert their effect at the cell body . Neurotrophic factors either maintain the viability of the neuron or induce specific effects such as axonal extension, sprouting and other responses to injury and disease. Examples include factors such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and related molecules as well as ciliary neurotrophic factor (CNTF), insulin like growth factor (IGF) and fibroblast growth factors (FGF's) that all have neurotrophic activity and are derived from neuronally associated tissues as diverse as muscle, Schwann cells and spinal cord astrocytes and other neurons (e.g., Nishi, Science (1994) 265:1052). The identification of pharmaceutical products or agents which induce the endogenous production of trophic factors would be beneficial treatment of diseases which involve trophic support. SUMMARY OF THE INVENTION In general, the present invention relates to methods of affecting cellular communication in a vertebrate. The communication is affected by the administration of a neuregulin to a vertebrate, where the neuregulin interacts with a first cell type which results in the production of a product or products (i.e., Product(s) A). This product, in turn, affects the function of a second cell type. (See FIGS. 9 and 10) Neuregulins are a family of protein factors encoded by one gene. A variety of messenger RNA splicing variants (and their resultant proteins) are derived from this gene and many of these products show binding and activation to erbB2 (neu) and closely related receptors erbB3 and erbB4. The invention provides methods for using all of the known products of the neuregulin gene, as well as, other not yet discovered splicing variants of the neuregulin gene. Methods also are provided by the invention in which the effect in function of the second cell type, as described above, results in the production of a second product (i.e., Product B) which, in turn, can affect the function of the first cell type or a third cell type. (See FIGS. 9 and 10) Included in the invention as well, are methods for treatment when disorders involve an altered or inadequate level of production of a product involved in cellular communication. Advantages of the present invention include the development of new therapeutic approaches to injury or disease based on the interdependence or communication of cells and the ability to influence or affect that communication with neuregulins. For example, a neuregulin factor that is produced by the second cell type can induce the first cell type to produce a product or products (Product(s) A) that are trophic for the second cell type. More specifically, cells and tissues that are associated with neurons may be induced to respond to a neuronally produced factor (neuregulin). This response would be in the form of the production of products (Product(s) A) that are trophic for neurons. The endogenous induction of more than one neurotrophic products by the neuregulin would be more effective than the therapeutic use of a single neurotrophic factor. Neurotrophic factors generally have restricted effects on specific neuronal subtypes (e.g. CNTF is trophic for motor neurons and NGF is trophic for sympathetic neurons as well as a subset of sensory neurons). Furthermore, the types of neurotrophic factors produced by a particular tissue are probably dependent on the target neuron type as well as the type and stage of injury. As an example, CNTF, which is trophic for motor neurons, is released by Schwann cells in the early stages of recovery from nerve injury. This is replaced within a few days by Schwann cell and muscle derived BDNF, another motor neuron trophic factor (Curtis, et al., Nature (1993) 365:253-255; and Funakoshi, et al, J. Cell Biol. (1993) 123:455-465). In addition multiple neurotrophic factors function in vivo and may be synergistic in their effects. For example, it has been shown that multiple factors more efficiently arrest disease induced neuronal degeneration in animals than the use of a single factor (Mitsumoto et al., Science (1994) 265:1107). In the central nervous system, the neuregulin target, the first cell type, could be a neuron that in turn produces Product(s) A. Product A then affects other tissues (the second cell type) that produce neurotrophic products (Product(s) B) that affect the second cell type (the second cell type may be the source of the neuregulin), or perhaps a third cell type. Thus, the use of the neuregulins, that are trophic for neuronally associated tissues in the manner described above would be therapeutically useful. Treatment would ensure the production of target specific combinations of products that are tailored to a particular disease state. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a schematic diagram showing the method used to set up the SCG (superior cervical ganglion)/culture tube experiments. FIG. 2 is a schematic diagram of the grid reticule inserted in the microscope ocular, which at a total magnification of 160.times., allowed quantification of Schwann cell outgrowth and neurite outgrowth for the SCG/culture tube experiments. FIG. 3A shows the control data, that is, Schwann cell number as a function of distance from the SCG explant, for the SCG /culture tube experiments. FIG. 3B shows experimental data, of Schwann cell outgrowth for the SCG/culture tube experiments, at a dosage of 5 ng/ml rhGGF2. FIG. 3C shows experimental data, of Schwann cell outgrowth for the SCG/culture tube experiments, at a dosage of 50 ng/ml rhGGF2. FIG. 3D shows experimental data, of Schwann cell outgrowth for the SCG/culture tube experiments, at a dosage of 500 ng/ml rhGGF2. FIG. 4 shows the total number of Schwann cells as a function of days in vitro for the SCG/culture tube experiments. FIG. 5 shows experimental data, of neurite outgrowth, as a function of distance from the SCG explant, for the SCG/culture tube experiments performed at dosage levels of 5,50 and 500 ng/ml rhGGF2. FIG. 6A shows a 2-dimensional dose-response matrix, used to examine the effects of rhGGF2 on neuronal survival and outgrowth. FIG. 6B illustrates the manner of counting, used in the afore-mentioned 2-dimensional dose-response experiment, by showing a representative sample well with fields of view. FIG. 7 shows experimental data of the effects of rhGGF2 on neuronal survival and outgrowth. FIG. 8A shows data on the effects of exogenous GGF on the number of myelinated axons at 28 days post-injury. FIG. 8B shows the above-referenced data in bar graph form. FIG. 9 represents a schematic illustration of the effect neuregulins can have on cellular communication. FIG. 10 represents a schematic illustration of specific effects of neuregulins on cellular communication. FIG. 11A is a listing of the coding strand DNA sequence (SEQ ID NO: 1) and deduced amino aid sequence (SEQ ID NO: 2) of the cDNA obtained from splicing pattern of GGF2BPP1 shown in FIG. 12. Potential glycosylation sites are underlined (along with polyadenylation signal AATAAA(SEQ ID NO: 75); FIGS. 11B-11C is a listing of the coding strand DNA sequence (SEQ ID NO: 3) and deduced amino acid sequence (SEQ ID NO: 4) of the cDNA obtained from splicing pattern of GGF2BPP2. Potential glycosylation sites are underlined (along with polyadenylation signal AATAAA(SEQ ID NO: 75); FIGS. 11D-11E is a listing of the coding strand DNA (SEQ ID NO: 5) sequence and deduced amino acid sequence (SEQ ID NO: 6) of the cDNA obtained from splicing pattern of GGF2BPP3. Potential glycosylation sites are underlined (along with polyadenylation signal AATAAA(SEQ ID NO: 75). FIG. 12 is a diagram of representative splicing variants. The coding segments are represented by F, E, B, A, G, C, C/D, C/D', D, D', H, K, and L. The location of the peptide sequences derived from purified protein are indicated by "o." FIGS. 13A-13R is a listing of the DNA sequences and predicted peptide sequences of the coding segments of GGF(SEQ ID NOs: 7-52). Line 1 is a listing of the predicted amino acid sequences of bovine GGF, line 2 is a listing of the nucleotide sequences of bovine GGF, line 3 is a listing of the nucleotide sequences of human GGF (heregulin) (nucleotide base matches are indicated with a vertical line) and line 4 is a listing of the predicted amino acid sequences of human GGF/heregulin where it differs from the predicted bovine sequence. Coding segments E, A' and K represent only the bovine sequences. Coding segment D' represents only the human (heregulin) sequence. FIGS. 14A-14B is the predicted GGF2 amino acid sequence (SEQ ID NO: 54) and nucleotide sequence (SEQ ID NO: 53) of BPP5. The upper line is the nucleotide sequence and the lower line is the predicted amino acid sequence. FIGS. 15A-15B is the predicted amino acid sequence (SEQ ID NO: 56) and nucleotide sequence (SEQ ID NO: 55) of GGF2BPP2. The upper line is the nucleotide sequence and the lower line is the predicted amino acid sequence. FIGS. 16A-16C is the predicted amino acid sequence (SEQ ID NO: 58) and nucleotide sequence (SEQ ID NO: 57) of GGF2BPP4. The upper line is the nucleotide sequence and the lower line is the predicted amino acid sequence. FIG. 17 is a list of splicing variants derived from the sequences shown in FIG. 13. FIG. 18 is the predicted amino acid sequence (SEQ ID NO: 60), bottom, and nucleotide sequence (SEQ ID NO: 59), top of EGFL1. FIG. 19 is the predicted amino acid sequence (SEQ ID NO: 62), bottom, and nucleotide sequence (SEQ ID NO: 61), top, of EGFL2. FIG. 20 is the predicted amino acid sequence (SEQ ID NO: 64), bottom, and nucleotide sequence (SEQ ID NO: 63), top, of EGFL3. FIG. 21 is the predicted amino acid sequence (SEQ ID NO: 66), bottom, and nucletide sequence (SEQ ID NO: 65), top, of EGFL4. FIG. 22 is the predicted amino acid sequence (SEQ ID NO: 68), bottom, and nucleotide sequence (SEQ ID NO: 67), top, of EGFL5. FIG. 23 is the predicted amino acid sequence (SEQ ID NO: 70), bottom, and nucleotide sequence (SEQ ID NO: 69), top, of EGFL6. FIG. 24 is the predicted amino acid sequence (SEQ ID NO: 72) (middle) and nucleotide sequence (SEQ ID NO: 71) (top) of GGF2HBS5. The bottom (intermittent) sequence represents peptide sequences derived from GGF-II preparations (SEQ ID NOs: 42, 45-53). FIG. 25 is the sequences of GGFHBS5 (SEQ ID NO: 72), GGFHB1 (SEQ ID NO: 73) and GGFBPP5 (SEQ ID NO: 74) polypeptides. FIG. 26 is the amino acid sequence of cDNA encoding mature hGGF2 (SEQ ID NO: 72). FIG. 27 depicts a stretch of the putative bovine GGF-II gene sequence from the recombinant bovine genomic phage GGF2BG1. The figure is the coding strand of the DNA sequence (SEQ ID NO: 76) and the deduced amino acid sequence in the third reading frame. DETAILED DESCRIPTION OF THE INVENTION It is intended that all references cited shall be incorporated herein by reference. General The invention pertains to methods of affecting cellular communication in vertebrates. The communication is affected by the administration of a neuregulin to a vertebrate where the neuregulin interacts with a first cell type which results in the production of a product. This product, in turn, affects the function of a second cell type. More specifically, the invention relates to the induction of endogenous tropic factors (products) by the administration of a neuregulin. Methods also are provided by the invention in which the affect in function of the second cell type, described above, results in the production of a second product which, in turn, can affect the function of the first cell type, the second cell type or a third cell type. Definition of Key Terms The term affecting as used herein refers to the induction of a quantitative change in the response of a target cell, as a result of an interaction with a Product. The term interacts as used herein refers to a contact with a target (cell), including but not limited to binding of a product to a cell receptor. The term cellular communication as used herein refers to the synthesis of a substance in one cell type and the interaction of that substance with a second cell type. This process includes but is not limited to secretion of the substance from a cell. The substance elicits a change in the second cell type or with the first cell type. Communication can occur reciprocally or non-reciprocally with one or more cell types. The term vertebrate as used herein refers to an animal that is a member of the Subphylum Vertebrata (Phylum Chordata). The term administration as used herein refers to a pharmaceutical preparation of a substance and the delivery of that preparation to a recipient. The term neuregulin as used herein refers to the glial growth factors, the heregulins, neu differentiation factor, acetylcholine receptor inducing activity, and erbB2, 3 and 4 binding proteins. A more complete definition of neuregulins can be found in the specification herein and in the following materials: U.S. Pat. No. 5,237,056; U.S. patent application Ser. No. 08/249,322; WO 92/20798; EPO 0 505 148 A1; Marchionni, et al., Nature 362:313, 1993; Benveniste, et al., PNAS82:3930-3934, 1985; Kimura, et al., Nature (1990) 348:257-260; Davis and Stroobant, J. Cell. Biol. (1990) 110:1353-1360; Wen, et al., Cell (1992) 69:559; Yarden and Ullrich, Ann. Rev. Biochem. (1988) 57:443,; Holmes, et al., Science 256:1205, 1992; Dobashi, et al., Proc. Natl. Acad. Sci. 88:8582, 1991; Lupu, et al., Proc. Natl. Acad. Sci. (1992) 89:2287; Peles and Yarden, BioEssays (1993) 15:815, Mudge, Current Biology (1993) 3:361, all hereby incorporated by reference. The term first cell type as used herein refers to the cell type that interacts with a neuregulin. The first cell type includes but is not limited to one or more of the following: neuron, glial cell, Schwann cell, astrocyte, oligodendrocyte, myoblast, muscle cell, satellite cell, skin cell, sensory organ cell, inflammatory cell such as macrophage, neutrophil, T-cell, eosinophil, mast cell, basophil and stromal cell such as fibroblasts or endothelial cells. Bloom and Fawcett, A Textbook of Histology, tenth ed. (1975), W. B. Saunders Company, Philadelphia, Pa. The term second cell type as used herein refers to the cell type that interacts with and responds to Product A. The second cell type includes but is not limited to one or more of the following: neuron, glial cell, Schwann cell, astrocyte, oligodendrocyte, myoblast, muscle cell, satellite cell, skin cell, sensory organ cell, inflammatory cell such as macrophage, neutrophil, T-cell, eosinophil, mast cell, basophil and stromal cell such as fibroblasts or endothelial cells. A more complete definition may be found in Bloom and Fawcett, A Textbook of Histology, tenth ed. (1975), W. B. Saunders Company, Philadelphia, Pa. The term third cell type as used herein refers to a cell type that interacts with and responds to Product B. The third cell type may be identical to the first cell type. The third cell type includes but is not limited to one or more of the following: neuron, glial cell, Schwann cell, astrocyte, oligodendrocyte, myoblast, muscle cell, satellite cell, skin cell, sensory organ cell, inflammatory cell such as macrophage, neutrophil, T-cell, eosinophil, mast cell, basophil and stromal cell such as fibroblasts or endothelial cells. A more complete definition may be found in Bloom and Fawcett, A Textbook of Histology, tenth ed. (1975), W. B. Saunders Company, Philadelphia, Pa. The term production as used herein refers to induced or constitutive synthesis and/or release of a Product from a cell. The term Product as used herein refers to any substance as defined herein as Product A or Product B. The term Product A as used herein refers to the substances whose synthesis and release are induced in the first cell type by neuregulin. Such substances include but are not limited to one or more of the following: nerve growth factor (NGF), neurotrophins, brain-derived neurotrophic factor, ciliary neurotrophic factor, leukemia inhibiting factor, interleukin 6, platelet derived growth factor, fibroblast growth factors, transforming growth factor .beta., epidermal growth factor, transforming growth factor .alpha., neuregulins, insulin like growth factor, matrix molecules, adhesion molecules, growth factor receptors, low affinity NGF receptor, proteases, protease inhibitors, and antioxidants. The term Product B as used herein refers to the substances whose synthesis and release are induced in the second cell type by Product A. Such substances include but are not limited to one or more of the following: nerve growth factor (NGF), neurotrophins, brain-derived neurotrophic factor, ciliary neurotrophic factor, leukemia inhibiting factor, interleukin 6, platelet derived growth factor, fibroblast growth factors, transforming growth factor .beta., epidermal growth factor, transforming growth factor .alpha., neuregulins, glial derived neurotrophic factor, insulin like growth factor, matrix molecules, adhesion molecules, growth factor receptors, low affinity NGF receptor (p75), proteases, protease inhibitors and antioxidants. The term function as used herein refers to any activity or response of a cell. These include but are not limited to proliferation, differentiation, growth, survival, changes in the pattern of gene expression and secretion, and metabolic changes. The term glial cell as used herein refers to connective and support tissues of the nervous system and includes ectodermally derived astrocytes, oligodendroglia, Schwann cells and mesodermally derived microglia and their progenitors. A more complete definition of glial cells and their progenitors can be found in the following materials: Anderson, FASEB J. (1994) 8:707-713; Reynolds and Weiss, Science (1992) 255:1707-1710; Reynolds, Tetzlaff, and Weiss, J. Neurosci (1992) 12:4565-4574; and Kandel, et al., Principles of Neuroscience, third ed. (1991), Appleton & Lange, Norwalk, Conn. The termastrocyte as used herein refers to a neuroglial cell of ectodermal origin and its progenitor cells. This cell has a round nucleus and a "star shaped" body and many long processes that end as vascular foot plates on the small blood vessels of the CNS and is associated with other structures. A more complete definition of astrocyte and its progenitors can be found in the following materials: Reynolds and Weiss, Science (1992) 255:1707-1710; Reynolds, Tetzlaff, and Weiss, J. Neurosci (1992) 12:4565-4574; and Kandel, et al., Principles of Neuroscience, third ed. (1991), Appleton & Lange, Norwalk, Conn. The term skin cell as used herein refers to the cellular components of the skin and includes fibroblasts, keratinocytes, epidermal cells, hair follicle cells, melanocytes, myoepithelial sweat gland cells, and sebaceous gland cells and their progenitors. A more complete definition of skin cells and their progenitors can be found in, Wheater, et al., Functional Histology (1987), Churchill Livingstone, New York, N.Y. The term Schwann cell as used herein refers to the neuroglial cell composing the neurolemma of peripheral nerve fibers and its progenitors. A more complete definition of Schwann cells and their progenitors can be found in the following materials: Anderson, FASEB J. (1994) 8:707-713; Kandel, et al., Principles of Neuroscience, third ed. (1991), Appleton & Lange, Norwalk, Conn. The term oligodendrocyte as used herein refers to the neuroglial cells, of ectodermal origin, with small oval nuclei and fine cytoplasmic processes that are responsible for the formation of myelin in the CNS. The progenitors of oligodendrocytes are also included. A more complete definition of oligodendrocytes and their progenitors can be found in, Kandel, et al., Principles of Neuroscience, third ed. (1991), Appleton & Lange, Norwalk, Conn. The term sensory organ cell as used herein refers to a primary sensory cell contained within a sensory organ and its progenitors and includes but is not limited to one or more of the following: taste cells, olfactory epithelial cell, rod and cone photoreceptors, Meisner corpuscle, Ruffini corpuscle, Merckel receptor, Pacinian corpuscle, muscle spindle cell, cochleovestibular hair cells and joint mechanoreceptor cells. A more complete definition of sensory organ cells and their progenitors can be found in, Wheater, et al., Functional Histology (1987), Churchill Livingstone, New York, N.Y.; Mahanthappa and Schwarting, Neuron (1993) 10:293-305; Forge, Li, Corwin and Nevill, Science (1993) 259:1616-1622; Tsue, Watling, Weisleder, Coltrera and Rubel, J. Neurosci (1994) 14:140-152. The term neurotrophic agent as used herein refers to a substance that elicits a trophic effect in one or more neuronal subtypes. These effects include but are not limited to survival, sprouting and differentiation. The term neuron as used herein refers to a complete nerve cell, including the cell body and all of its processes, and its progenitors. A more complete definition of neuron and its progenitors can be found in the following materials: Reynolds and Weiss, Science (1992) 255:1707-1710; Reynolds, Tetzlaff, and Weiss, J. Neurosci (1992) 12:4565-4574; Ray, Peterson, Schinstine, and Gage, PNAS (1993) 90:3602-3606; and Kandel, et al., Principles of Neuroscience, third ed. (1991), Appleton & Lange, Norwalk, Conn. The term matrix molecule as used herein refers to a chemical component of the insoluble meshwork of extracellular proteins that mediate adhesive interactions between cells and modulate the functions of cells. The term muscle cell as used herein refers to a cellular component of skeletal, smooth or cardiac muscle, including but not limited to myofibrils, satellite cells, and myoepithelial cells and their progenitors. A more complete definition of muscle cells can be found in, Wheater, et al., Functional Histology (1987), Churchill Livingstone, New York, N.Y.; and Myology, ed. by Engel and Franzini-Armstrong, second ed. (1994) McGraw Hill, New York, N.Y. The term protease as used herein refers to an enzyme that hydrolyses peptide bonds in a protein molecule. The term protease inhibitor as used herein refers to a molecule that inhibits the activity and/or function of a protease. The term differentiation as used herein refers to a morphological and/or chemical change that results in the generation of a different cell type or state of specialization. The differentiation of cells as used herein refers to the induction of a cellular developmental program which specifies one or more components of a cell type. The therapeutic usefulness of differentiation can be seen, in increases in quantity of any component of a cell type in diseased tissue by at least 10% or more, more preferably by 50% or more, and most preferably by more than 100% relative to the equivalent tissue in a similarly treated control animal. The term mitosis as used herein refers to the division of a cell where each daughter nucleus receives identical complements of the numbers of chromosomes characteristic of the somatic cells of the species. Mitosis as used herein refers to any cell division which results in the production of new cells in the patient. More specifically, a useful therapeutic is defined in vitro as an increase in mitotic index relative to untreated cells of 50%), more preferably 100%, and most preferably 300%, when the cells are exposed to labeling agent for a time equivalent to two doubling times. The mitotic index is the fraction of cells in the culture which have labeled nuclei when grown in the presence of a tracer which only incorporates during S phase (i.e., BrdU) and the doubling time is defined as the average time required for the number of cells in the culture to increase by a factor of two. An effect on mitosis in vivo is defined as an increase in satellite cell activation as measured by the appearance of labeled satellite cells in the muscle tissue of a mammal exposed to a tracer which only incorporates during S phase (i.e., BrdU). A useful therapeutic is defined in vivo as a compound which increases satellite cell activation relative to a control mammal by at least 10%, more preferably by at least 50%, and most preferably by more than 200% when the mammal is exposed to labeling agent for a period of greater than 15 minutes and tissues are assayed between 10 hours and 24 hours after administration of the mitogen at the therapeutic dose. The term survival as used herein refers to any process where a cell avoids death. The term survival as used herein also refers to the prevention of cell loss as evidenced by necrosis or apoptosis or the prevention of other mechanisms of cell loss. Survival as used herein indicates a decrease in the rate of cell death of at least 10%, more preferably by at least 50%, and most preferably by the least 300% relative to an untreated control. The rate of survival may be measured by counting cells stainable with a dye specific for dead cells (such as propidium iodide) in culture when the cells are 8 days post-differentiation (i.e., 8 days after the media is changed from 20% to 0.5% serum). The term disorder as used herein refers to a disturbance of function and/or structure of a living organism, resulting from an external source, a genetic predisposition, a physical or chemical trauma, or a combination of the above, including but not limited to any mammalian disease. The term treating as used herein may refer to a procedure (e.g. medical procedure) designed to exert a beneficial effect on a disorder. Treating as used herein means any administration of a substance described herein for the purpose of increasing cellular communication of products. Most preferably, the treating is for the purpose of reducing or diminishing the symptoms or progression of a disease or disorder of cells. Treating as used herein also means the administration of a substance to increase or alter the cells in healthy individuals. The treating may be brought about by the contacting of the cells which are sensitive or responsive to the neuregulins described herein with an effective amount of the neuregulin. The term mammal as used herein describes a member of the Class Mammalia (Subphylum Vertebrata). The term neurological disorder as described herein refers to a disorder of the nervous system. The term administration as used herein refers to the act of delivering a substance, including but not limited to the following routes: parenteral, intravenous, subcutaneous, intramuscular, intraorbital, ophthalmic, intraventricular, intracranial, intracapsular, intraspinal, intracisternal, intraperitoneal, topical, intranasal, aerosol, scarification, orally, buccal, rectal or vaginal. The term therapeutically effective amount as used herein refers to that amount which will produce a desirable result upon administration and which will vary depending upon a number of issues, including the dosage to be administered, and the route of administration. The term peripheral neuropathy as used herein refers to functional disturbances and/or pathological changes in the peripheral nervous system. The term amyotrophic lateral sclerosis (ALS) as used herein refers to a motor neuron disease characterized by a progressive degeneration of the neurons that give rise to the corticospinal tract that results in a deficit in upper and lower motor neurons. The term spinal muscular atrophy as used herein refers to a progressive disease of upper and lower motor neurons, usually present in childhood. The term Alzheimer's Disease as used herein refers to a progressive central neurodegeneration involving loss of cortical and other neurons, and associated with neurofibrillary tangles and .beta.-amyloid deposits. The term Parkinson's Disease as used herein refers to a progressive central neurodegeneration involving dopaminergic neurons. The term trophic as used herein refers to an effect of a substance on a cell, including but not limited to proliferation, growth, sprouting, differentiation or survival. The term neuregulin producing cell as used herein refers to a cell that produces a neuregulin. The term refers to all producer cells including cells that produce recombinant neuregulins. The term nervous system cell as used herein includes nervous system support cells and neurons. Neuregulins A novel aspect of the present invention relates to the ability of neuregulins to affect cellular communication between different and similar cell types. Neuregulins are the products of a gene which produce a number of variably-sized, differentially-spliced RNA transcripts that give rise to a series of proteins. These proteins are of different lengths and contain some common peptide sequences and some unique peptide sequences. The conclusion that these factors are encoded by a single gene is supported by the differentially-spliced RNA sequences which are recoverable from bovine posterior pituitary, human spinal chord and human breast cancer cells (MDA-MB-231). Further support for this conclusion derives from the size range of proteins which act as ligands for the p185.sup.erbB2 receptor (see below). Further evidence to support the fact that the genes encoding GGF/p185.sup.erbB2 binding proteins are homologous comes from nucleotide sequence comparison. Holmes et al., (Science (1992) 256:1205-1210) demonstrate the purification of a 45-kilodalton human protein (Heregulin-.alpha.) which specifically interacts with the receptor protein p185.sup.erbB2. Peles et al., (Cell (1992) 69:559) describe a complementary DNA isolated from rat cells encoding a protein call "neu differentiation factor" (NDF). The translation product of the NDF cDNA has p185.sup.erbB binding activity. Several other groups have reported the purification of proteins of various molecular weights with p185.sup.erbB2 binding activity. These groups include the following: Lupu et al., (1992) Proc. Natl. Acad. Sci. USA 89:2287; Yarden and Peles, (1991) Biochemistry 30:3543; Lupu et al., (1990) Science 249:1552; Dobashi et al., (1991) Biochem. Biophys. Res. Comm. 179:1536; and Huang et al., (1992) J. Biol. Chem. 257:11508-11512. We have found that p185.sup.erbB2 and related receptor binding proteins (i.e., p185.sup.erbB3 and p185.sup.erbB4) affect cellular communication. This effect results in the production of a product from a first cell type, where the product, in turn affects the function of a second cell type. The affect in a function of the second cell type and can result in the production of other products which also can affect functions of other cell types. For example, neuregulins can interact with Schwann cells, which as a result of this interaction produce neurotrophic agents. These agents, in turn, interact with neurons to promote their neuronal regeneration. Alternatively, in the central nervous system, a first cell type, being a neuron, could produce a neuregulin, which in turn, affects a second cell type which is a neuron also. These neuregulins may be identified using the protocols described herein (Examples 1 and 2) and in Holmes et al., Science (1992) 256: 1205; Peles et al., Cell (1992) 69:205; Wen et al., Cell (1992) 69:559; Lupu et al., Proc. Natl. Acad. Sci. USA (1992) 89:2287; Yarden and Peles, Biochemistry (1991) 30:3543; Lupu et al., Science (1990) 249:1552; Dobashi et al., Biochem. Biophys. Res. Comm. (1991) 179:1536; Huang et al., J. Biol. Chem. (1992) 257:11508-11512; Marchionni et al., Nature (1993) 362:313; and in U.S. patent application Ser. No. 07/931,041, filed Aug. 17, 1992, all of which are incorporated herein by reference. Specifically, the invention provides for use of polypeptides of a specified formula, and DNA sequences encoding those polypeptides. The polypeptides have the formula WYBAZCX wherein WYBAZCX is composed of the amino acid sequences shown in FIGS. 13A-13D and 13F-13R (SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, and 52); wherein W comprises the polypeptide segment F, or is absent; wherein Y comprises the polypeptide segment E, or is absent; wherein Z comprises the polypeptide segment G or is absent; and wherein X comprises the polypeptide segments C/D HKL, C/D H, C/D HL, C/D D, C/D' HL, C/D' HKL, C/D' H, C/D' D, C/D C/D' HKL, C/D C/D' H, C/D C/D' HL, C/D C/D' D, C/D D' H, C/D D' HL, C/D D' HKL, C/D' D' H, C/D' D' HL, C/D' D' HKL, C/D C/D' D' H, C/D C/D' D' HL, or C/D C/D' D' HKL; provided that, either a) at least one of F, Y, B, A, Z, C, or X is of bovine origin; or b) Y comprises the polypeptide segment E; or c) X comprises the polypeptide segments C/D HKL, C/D D, C/D' HKL, C/D C/D' HKL, C/D C/D' D, C/D D' H, C/D D' HL, C/D D' HKL, C/D' D' H, C/D' D' HKL, C/D C/D' D' H, C/D C/D' D' HL, C/D C/D' D' HKL, C/D' H, C/D C/D' H, or C/D C/D' HL. In addition, the invention includes the use of the DNA sequence comprising coding segments .sup.5' FBA.sup.3' as well as the with corresponding polypeptide segments having the amino acid sequences shown in FIGS. 13A, 13C, and 13D (SEQ ID NOs: 7-10 and 13-20); the DNA sequence comprising the coding segments .sup.5' FBA'.sup.3' as well as the corresponding polypeptide segments having the amino acid sequences shown in FIGS. 13A, 13C, and 13E (SEQ ID NOs; 7-10, 13-16, 21, and 22); the DNA sequence comprising the coding segments .sup.5' FEBA'.sup.3' as well as the corresponding polypeptide segments having the amino acid sequences shown in FIGS. 13A-13D and 13R (SEQ ID NOs: 7-20, 51, and 52); the DNA sequence comprising the coding segments .sup.5' FEBA'.sup.3' as well as the corresponding polypeptide segments having the amino acid sequences shown in FIGS. 13A-13C, 13E, and 13R (SEQ ID NOs: 7-16, 21, 22, 51, and 52). the DNA sequence comprising the polypeptide coding segments of the GGF2HBS5 cDNA clone (ATCC Deposit No. 75298, deposited Sep. 2, 1992), also known as GGF-II (SEQ ID NO: 72). The invention further includes the use of peptides of the formula FBA, FEBA, FBA' FEBA' and DNA sequences encoding these peptides wherein the polypeptide segments correspond to amino acid sequences shown in FIGS. 13A-13E and 13R (SEQ ID NOs: 7-10 and 13-20), (SEQ ID NOs; 7-10, 13-16, 21, and 22), (SEQ ID NOs: 7-20, 51, and 52), and (SEQ ID NOs: 7-20, 51, and 52). The polypeptide purified GGF-II polypeptide (SEQ ID NO: 72) is also included as part of the invention. Also included in this invention is the mature GGF peptide and the DNA encoding said peptide, exclusive of the N-terminal signal sequence, which is also useful for treatment of conditions involving abnormalities in cellular communication. Furthermore, the invention includes a method of cellular communication by the application to a vertebrate of a -30 kD polypeptide factor isolated from the MDA-MB 231 human breast cell line; or -35 kD polypeptide factor isolated from the rat I-EJ transformed fibroblast cell line to the glial cell; or -75 kD polypeptide factor isolated from the SKBR-3 human breast cell line; or -44 kD polypeptide factor isolated from the rat I-EJ transformed fibroblast cell line, or -25 kD polypeptide factor isolated from activated mouse peritoneal macrophages; or -45 kD polypeptide factor isolated from the MDA-MB 231 human breast cell; or -7 to 14 kD polypeptide factor isolated from the ATL-2 human T-cell line to the glial cell; or -25 kD polypeptide factor isolated from the bovine kidney cell; or -42 kD polypeptide factor (ARIA) isolated from brains. The invention further includes a method for the use of the EGFL1, EGFL2, EGFL3, EGFL4, EGFL5, and EGFL6 polypeptides, FIG. 18 to 23 and (SEQ ID NOs: 60, 62, 64, 66, 68 and 70) respectively, for the methods of affecting cellular communication in vivo and in vitro. Also included in the invention is the administration of the GGF-II polypeptide whose sequence is shown in FIG. 24 (SEQ ID NO: 72) for affecting cellular communication. An additional aspect of the invention includes the use of the above-referenced peptides for the purpose of stimulating Schwann cells to produce growth factors which may, in turn, be harvested for scientific or therapeutic use. Thus, the invention further embraces a polypeptide factor capable of affecting cellular communication and including an amino acid sequence encoded by: (a) a DNA sequence shown in FIG. 11A-11E (SEQ ID NOs: 1,3, and 5); (b) a DNA sequence shown in FIG. 27 (SEQ ID NO: 76); (c) the DNA sequence represented by nucleotides 281-557 of the sequences shown in FIG. 11A-11E (SEQ ID NOs: 1,3, and 5); or (d) a DNA sequence hybridizable to any one of the DNA sequences according to (a), (b) or (c). The invention further includes sequences which have greater than 60%, preferably 80%, sequence identity of homology to the sequences indicated above. While the present invention is not limited to a particular set of hybridization conditions, the following protocol gives general guidance which may, if desired, be followed: DNA probes may be labeled to high specific activity (approximately 10.sup.8 to 10.sup.9 32 Pdmp/.mu.g) by nick-translation or by PCR reactions according to Schowalter and Sommer (Anal. Biochem. (1989) 177:90-94) and purified by desalting on G-150 Sephadex columns. Probes may be denatured (10 minutes in boiling water followed by immersion into ice water), then added to hybridization solutions of 80% buffer B (2 g polyvinylpyrolidine, 2 g Ficoll-400, 2 g bovine serum albumin, 50 ml 1 M Tris HCL (pH 7.5), 58 g NaCl, 1 g sodium pyrophosphate, 10 g sodium dodecyl sulfate, 950 ml H.sub.2 O) containing 10% dextran sulfate at 10.sup.6 dpm .sup.32 P per ml and incubated overnight (approximately 16 hours) at 60.degree. C. The filters may then be washed at 60.degree. C. first in buffer B for 15 minutes followed by three 20-minute washes in 2.times.SSC, 0.1% SDS then one for 20 minutes in 1.times.SSC, 0.1% SDS. In other respects, the invention provides: (a) a basic polypeptide factor which has, if obtained from bovine pituitary material, an observed molecular weight, whether in reducing conditions or not, of from about 30 kD to about 36 kD on SDS-polyacrylamide gel electrophoresis using the following molecular weight standards: ______________________________________ Lysozyme (hen egg white) 14,400 Soybean trypsin inhibitor 21,500 Carbonic anhydrase (bovine) 31,000 Ovalbumin (hen egg white) 45,000 Bovine serum albumin 66,200 Phosphorylase B (rabbit muscle) 97,400; ______________________________________ which factor has glial cell mitogenic activity including stimulating the division of rat Schwann cells in the presence of fetal calf plasma, and when isolated using reversed-phase HPLC retains at least 50% of said activity after 10 weeks incubation in 0.1% trifluoroacetic acid at 4.degree. C.; and (b) a basic polypeptide factor which has, if obtained from bovine pituitary material, an observed molecular weight, under non-reducing conditions, or from about 55 kD to about 63 kD on SDS-polyacrylamide gel electrophoresis using the following molecular weight standards: ______________________________________ Lysozyme (hen egg white) 14,400 Soybean trypsin inhibitor 21,500 Carbonic anhydrase (bovine) 31,000 Ovalbumin (hen egg white) 45,000 Bovine serum albumin 66,200 Phosphorylase B (rabbit muscle) 97,400; ______________________________________ which factor the human equivalent of which is encoded by DNA clone GGF2HBS5 described herein and is capable of affecting cellular communication. For convenience of description only, the lower molecular weight and higher molecular weight factors of this invention are referred to hereafter as "GGF-I" and "GGF-II", respectively. The "GGF2" designation is used for all clones isolated with peptide sequence data derived from GGF-II protein (i.e., GGF2HBS5, GGF2BPP3). It will be appreciated that the molecular weight range limits quoted are not exact, but are subject to slight variations depending upon the source of the particular polypeptide factor. A variation of, say, about 10% would not, for example, be impossible for material from another source. Another important aspect of the invention is a DNA sequence encoding a polypeptide capable of affecting cellular communication and comprising: (a) a DNA sequence shown FIG. 11A-11E (SEQ ID NOs: 1,3, and 5); (b) a DNA sequence shown in FIG. 27 (SEQ ID NO: 76); (c) the DNA sequence represented by nucleotides 281-557 of the sequence shown in FIG. 11A-11E (SEQ ID NO: 1,3, and 5); or (d) a DNA sequence hybridizable to any one of the DNA sequences according to (a), (b) or (c). Thus other important aspects of the invention are: (a) A series of human and bovine polypeptide factors capable of affecting cellular communication. These peptide sequences are shown in FIGS. 13, 14, 15 and 16 (SEQ ID NOs: 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, and 58) respectively. (b) A series of polypeptide factors capable of affecting cellular communication and purified and characterized according to the procedures outlined by Lupu et al., Science (1990) 249:1552; Lupu et al., Proc. Natl. Acad. Sci USA (1992) 89: 2287; Holmes et al., Science (1992) 256:1205; Peles et al., Cell (1992) 69:205; Yarden and Peles, Biochemistry (1991) 30:3543; Dobashi et al., Proc. Natl. Acad. Sci. (1991) 88: 8582; Davis et al., Biochem. Biophys. Res. Commun. (1991) 179:1536; Beaumont et al., Patent Application PCT/US91/03443 (1990); Greene et al., Patent Application PCT/US91/02331 (1990); Usdin and Fischbach, J. Cell. Biol. (1986) 103:493-507; Falls et al., Cold Spring Harbor Symp. Quant. Biol. (1990) 55:397-406; Harris et al., Proc. Natl. Acad. Sci. USA (1991) 88:7664-7668; and Falls et al., Cell (1993) 72:801-815. (c) A polypeptide factor (GGFBPP5) is capable of affecting cellular communication. The amino acid sequence is shown in FIG. 14A-14B (SEQ ID NO: 54), and is encoded by the bovine DNA sequence shown in FIG. 14A-14B (SEQ ID NO: 53). The novel human peptide sequences described above and presented FIGS. 13, 14, 15, and 16 in FIGS. 13A, 13C, 13D, 13F-13M, 13O-13R (SEQ ID NOs: 10, 16, 20, 26, 30, 34, 36, 38, 40, 44, 50, and 52), respectively, represent a series of splicing variants which can be isolated as full length complementary DNAs (cDNAs) from natural sources (cDNA libraries prepared from the appropriate tissues) or can be assembled as DNA constructs with individual exons (e.g., derived as separate exons) by someone skilled in the art. Other compounds in particular, peptides, which bind specifically to the p185.sup.erbB2 receptor and related receptors can also be used according to the invention as affections of cellular communication. A candidate compound can be routinely screened for p185.sup.erbB2 binding, and, if it binds, can then be screened for affecting cellular communication using the methods described herein. The invention includes any modifications or equivalents of the above polypeptide factors which do not exhibit a significantly reduced activity. For example, modifications in which amino acid content or sequence is altered without substantially adversely affecting activity are included. By way of illustration, in EP-A 109748 mutations of native proteins are disclosed in which the possibility of unwanted disulfide bonding is avoided by replacing any cysteine in the native sequence which is not necessary for biological activity with a neutral amino acid. The statements of effect and use contained herein are therefore to be construed accordingly, with such uses and effects employing modified or equivalent factors being part of the invention. The new sequences of the invention open up the benefits of recombinant technology. The invention thus also includes the following aspects: |
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