Structural diversity and evolution of human receptor-like protein tyrosine phosphatases.

Abstract

Protein tyrosine phosphatases (PTPases), together with protein tyrosine kinases, regulate the tyrosine phosphorylation that controls cell activities and proliferation. Previously, it has been recognized that both cytosolic PTPases and membrane associated, receptor‐like PTPases exist. In order to examine the structural diversity of receptor‐like PTPases, we isolated human cDNA clones that cross‐hybridized to a Drosophila PTPase cDNA clone, DPTP12, under non‐stringent hybridization conditions. The cDNA clones thus isolated included LCA and six other novel receptor‐like PTPases, named HPTP alpha, beta, gamma, delta, epsilon, and zeta. The cytoplasmic regions of HPTP alpha and epsilon are highly homologous, and are composed of two tandemly duplicated PTPase‐like domains. The extracellular regions of HPTP alpha and epsilon are, respectively, 123 amino acids and 27 amino acids, and do not have obvious similarity to any known protein. The cytoplasmic region of HPTP beta contains only one PTPase domain. The extracellular region of HPTP beta, which is 1599 amino acids, is composed of 16 fibronectin type‐III repeats. HPTP delta is very similar to leukocyte common antigen related molecule (LAR), in both the extracellular and cytoplasmic regions. Partial sequences of HPTP gamma and zeta indicate that they are highly homologous and contain two PTPase‐like domains. The PTPase‐like domains of HPTP alpha, beta and delta expressed in Escherichia coli had tyrosine phosphatase activities.

A novel human ERK phosphatase regulates H-ras and v-raf signal transduction

“…A subfamily of protein tyrosine phosphatases (PTPs) related to the vaccinia virus-encoded phosphatase VH1 share a characteristic active site sequence VXVHCXXGXXR (known as an`HC motif'; Charbonneau et al, 1989;Krueger et al, 1990) within their catalytic domains, and e ciently hydrolyze both phosphotyrosine and phosphoserine (Guan et al, 1991). Many of these dual-speci®city PTPs (dsPTPs) have been implicated in the regulation of cell proliferation: cdc25 dephosphorylates and activates the cdc2 kinase, stimulating mitosis (Dunphy and Kumagai, 1991;Gautier et al, 1991;Millar et al, 1991); KAP/cdil interacts with the cyclin-dependent kinases CDK2 and cdc2 (Hannon et al, 1994;Gyuris et al, 1995); and disruption of the yeast VH1 gene results in growth retardation (Guan et al, 1992).…”

Substrate specificities of catalytic fragments of protein tyrosine phosphatases (HPTPβ, LAR, and CD45) toward phosphotyrosylpeptide substrates and thiophosphotyrosylated peptides as inhibitors

“…trast to two tandem repeats in CD45/LCA (Ralph et al, 1987;Tonks et al, 1988a), LAR (Streuli et al, 1988), and PTPa, y, 6, E , and { (Krueger et al, 1990). We have recently expressed the tandem repeat catalytic domains of CD45 and human LAR in single (Dl) and double (DlD2) forms, purified them, and determined that the phosphoenzyme intermediate in the pure LAR-Dl fragment is catalytically competent in phosphotyrosyl peptide hydrolysis, and its covalent attachment is to the thiolate side chain of the conserved cysteine, Cys 1,522 of LAR (Cho et al, 1992a,b).…”

Fibronectin type III‐like sequences and a new domain type in prokaryotic depolymerases with insoluble substrates

“…Amino acich in the individual sequences, which are identical to the consensus sequence, are also shown in bold. Partial comensus sequences of Fn3's in fibroneetin [26], titin [23], twitehin [24], eytotaetin [25], a protein-tyrosin© phosphata~¢ [27] and s~vcral cytokine receptors [281are shown below. A total con~nsus sequence (bottom) was constructed by showing residues conserved in at least 4 of the individual consensus sequences, with completely conserved re,~idugs in bold.…”

“…1). The latter and a proline are also conserved in FnYs of the eukaryotie proteins: titin [23], twitchin [24], cytotactin [25], fibron~tin [26], a protein-tyrosin¢ phosphatase [27] and several eytokiae receptors [28].…”