Roles of the Complex Formation of SHPS-1 with SHP-2 in Insulin-stimulated Mitogen-activated Protein Kinase Activation

Abstract

SHPS-1 is a receptor-like protein that undergoes tyro-

v-Src suppresses SHPS-1 expression via the Ras-MAP kinase pathway to promote the oncogenic growth of cells

“…SHP-2 is proposed as a positive mediator of cell growth and its recruitment to the plasma membrane upon growth stimulation has been observed (Stein-Gerlach et al, 1998). Takada et al (1998) reported that overexpression of SHPS-1 enhanced insulin-induced activation of MAP kinase, and mutation in tyrosine residues, Tyr449 and Tyr473, abolished the tyrosine phosphorylation of SHPS-1, its association with SHP-2 and activation of MAP kinase. In this study, however, we showed evidence that tyrosine phosphorylation of SHPS-1 was elevated in c-Src3Y1, G2E3Y1 and G2A3Y1, all of which are not transformed, while net amount of tyrosine phosphorylated SHPS-1 was substantially decreased in SR3Y1 (Figure 6a).…”

“…SHPS-1 is a receptor-like protein associated with protein tyrosine phosphatases with two SH2 domains, SHP-1 and SHP-2. SHPS-1 has three immunoglobulin-like domains in its extracellular region and four YXX(L/V/I) motifs, tyrosine phosphorylation sites of which Tyr449 and Tyr473 are critical for SHP-2 binding, in its cytoplasmic region (Takada et al, 1998). Various mitogens such as epidermal growth factor (EGF), insulin and platelet derived growth factor (PDGF) induced tyrosine phosphorylation of SHPS-1 and its association with SHP-2.…”

“…Various mitogens such as epidermal growth factor (EGF), insulin and platelet derived growth factor (PDGF) induced tyrosine phosphorylation of SHPS-1 and its association with SHP-2. Takada et al (1998) reported that overexpression of wild-type SHPS-1 signi®cantly increased mitogen-activated protein kinase (MAP kinase) activity in response to insulin, while overexpression of mutant SHPS-1 lacking SHP-2-binding sites markedly inhibited the MAP kinase activation. In contrast, Kharitonenkov et al (1997) reported that overexpression of SIRPa1, a human homologue of SHPS-1, inhibited the activation of MAP kinase by insulin or EGF and the cell transformation by v-fms.…”

Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs)

“…Investigation of mechanisms of PTP binding to ITIM motifs may shed light on PTP functional regulation, since little is known regarding the recruitment and activation of PTPs under physiologic conditions. SIRP/SHPS-1 proteins are tyrosine phosphorylated in response to EGF and insulin, and were originally identi®ed in anti-SHP2 immunoprecipitates (Fujioka et al, 1996;Kharitonenkov et al, 1997;Takada et al, 1998). Integrin signaling also increases SHPS-1 tyrosine phosphorylation and SHP2 binding , suggesting that SIRP/SHPS-1 proteins modulate cell signaling in response to both soluble growth factors and cell adhesion.…”

“…Collectively, these ®ndings suggest that multiple RTK-induced pathways may be downstream targets of SIRP. SIRP has been experimentally shown to modulate signaling of many RTKs, including the insulin receptor and the Epidermal Growth Factor Receptor (EGFR) (Kharitonenkov et al, 1997;Takada et al, 1998). SIRP tyrosine phosphorylation and subsequent recruitment of SHP2 to the plasma membrane have been shown to be related to SIRP functional regulation of RTK signaling (Cambier, 1997;Kharitonenkov et al, 1997).…”