Phosphotyrosyl protein phosphatases.

Enzyme-catalysed reversible protein phosphorylation is an important cellular regulatory mechanism (Nimmo & Cohen, 1977; Krebs & Beavo, 1979). Regulatory protein phosphorylation occurs most frequently on seryl and threonyl residues (Taborsky, 1974), and less frequently, on tyrosyl residues (Hunter, 1982). Protein phosphotyrosine [Tyr(P)] normally accounts for only 0.01-0.050o of the total protein phosphoamino acid content of a normal cell (Hunter & Sefton, 1980), but this value increases to 1-3 when the cells are infected with viruses (Sefton et al., 1981; Martensen, 1982). In the last several years much attention has been focused on the phosphotyrosyl phosphorylation of cellular proteins by specific phosphotyrosyl kinases, and phosphotyrosyl phosphorylations have been associated with the regulation of cellular activities, including proliferation, differentiation, and transformation (Hunter & Sefton, 1982; Heldin & Westermark, 1984; Sefton & Hunter, 1984; Swarup et al., 1984; Sefton, 1985; Coughlin et al., 1988). The suggested association between phosphotyrosyl phosphorylation and cell proliferation was further supported by studies which showed that a number of polypeptide growth factor receptors [i.e. epidermal growth factor (EGF), platelet-derived growth factor, insulin-like growth factor-i, insulin, etc.] possess intrinsic phosphotyrosyl kinase activities that are activated when the growth factors are bound, and that the activation of the receptor phosphotyrosyl kinases is essential for the action of the growth factors (Cohen et al. 1980; Ek et al., 1982; Jacobs et al., 1983; Reynolds et al., 1981; Sefton & Hunter, 1984; Gammeltoft & Van Obberghen, 1986). Moreover, many oncogene products also act as phosphotyrosyl kinases, and share extensive sequence homology with several polypeptide growth factor receptors (Heldin & Westermark, 1984; Sefton, 1985; Pimental, 1987). Studies using site-directed mutagenesis (Chou et al., 1987; Kmiecik & Shalloway, 1987) and specific anti-(receptor phosphotyrosyl kinase) antibodies (Morgan et al., 1986; Morgan & Roth, 1987) have indicated that the phosphotyrosyl kinase activity of growth factor receptors is an essential component for the biological action of the growth factors and of the transforming proteins (Kmiecik & Shalloway, 1987). Together, these observations have led to the general conclusion that increased cellular phosphorylation of protein tyrosyl residues plays an important role in the action of growth factors and also serve to regulate the cellular growth processes in general (Hunter & Cooper, 1983). In order for phosphotyrosyl phosphorylation system to serve an important physiological regulatory mechanism, the process must be reversible [i.e. a process for removing the phosphate (Pi) from the phosphotyrosyl residues must exist]. The enzyme activities responsible for dephosphorylating phosphotyrosyl proteins are known as phosphotyrosyl protein phosphatases (PTPP). If phosphotyrosyl phosphorylation represents a general physiological regulatory mechahnism, it is reasonable to expect that the overall phosphQtyrosyl phosphorylation levels in cells are regulated by the balance of the activities of both phosphotyrosyl kinases and PTPPs. Thus, to achieve a complete understanding of the significance of this reversible enzymic covalent modification, it is necessary to know the nature and the regulation of, not only phosphotyrosyl kinases, but also PTPPs. The enzymology of phosphotyrosyl kinases has been intensively investigated (Brugge & Chinkers, 1983) and extensively reviewed (Sefton & Hunter, 1984; Hunter & Cooper, 1985; Sefton, 1985). However, relatively little is known of the nature of the PTPPs (Foulkes, 1983). Consequently, we will focus this review on the current status of our understanding of the nature and regulation of the PTPP activities. We will also summarize the recent evidence suggesting a physiological role for PTPP activity in the regulation of normal bone cell growth.