PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis

Abstract

PSM/SH2-B has been described as a cellular partner of the FceRI receptor, insulin receptor (IR), insulin-like growth factor-I (IGF-I) receptor (IGF-IR), and nerve growth factor receptor (TrkA). A function has been proposed in neuronal dierentiation and development but its role in other signaling pathways is still unclear. To further elucidate the physiologic role of PSM we have identi®ed additional mitogenic receptor tyrosine kinases as putative PSM partners including platelet-derived growth factor (PDGF) receptor (PDGFR) beta, hepatocyte growth factor receptor (Met), and ®broblast growth factor receptor. We have mapped Y740 as a site of PDGFR beta that is involved in the association with PSM. We have further investigated the putative role of PSM in mitogenesis with three independent experimental strategies and found that all consistently suggested a role as a positive, stimulatory signaling adapter in normal NIH3T3 and baby hamster kidney ®broblasts. (1) PSM expression from cDNA using an ecdysone-regulated transient expression system stimulated PDGF-BB-, IGF-I-, and insulin-but not EGF-induced DNA synthesis in an ecdysone dose-responsive fashion; (2) Microinjection of the (dominant negative) PSM SH2 domain interfered with PDGF-BB-and insulin-induced DNA synthesis; and (3) A peptide mimetic of the PSM Prorich putative SH3 domain-binding region interfered with PDGF-BB-, IGF-I-, and insulin-but not with EGFinduced DNA synthesis in NIH3T3 ®broblasts. This experiment was based on cell-permeable fusion peptides with the Drosophila antennapedia homeodomain which eectively traverse the plasma membrane of cultured cells. These experimental strategies independently suggest that PSM functions as a positive, stimulatory, mitogenic signaling mediator in PDGF-BB, IGF-I, and insulin but not in EGF action. This function appears to involve the PSM SH2 domain as well as the Pro-rich putative SH3 domain binding region. Our ®ndings support the model that PSM participates as an adapter in various mitogenic signaling mechanisms by linking an activated (receptor) phospho-tyrosine to the SH3 domain of an unknown cellular partner. Oncogene (2000) 19, 39 ± 50.

Clinical Significance of SH2B1 Adaptor Protein Expression in Non-small Cell Lung Cancer

“…Although close association between SH2B1 expression and NSCLC metastasis has been established in our study, the possible mechanisms are still unclear that needed further investigations. Recent some studies have suggested that SH2B1 participate in tumor metastasis through its regulation of processes intrinsic to tumor cells and the surrounding tumor microenvironment depending on the interaction with multiple ligand-activated receptor tyrosine kinases, PDGF , IGF-I , FGFR3 , leptin and so on (Tsuchiya et al, 1999;Riedel et al, 2000;Yousaf et al, 2001;Kong et al, 2002;Somasundar et al, 2004), which may be a good illumination to tumor metastasis. In addition, the results of 108 archival NSCLC patients investigated by immunohistochemistry revealed that high SH2B1 expression level was closely associated with tumor grade, tumor size, clinical stage, lymph node metastasis and recurrence, which indicated the importance of SH2B1 in NSCLC progression and metastasis after surgical resection.…”

“…SH2B1 interacts with the activation loop of TrkA and plays a specific role in TrkA-mediated differentiation in human neuroblastoma cells , as well as axonal survival in primary sympathetic neurons (Eggert et al, 2000). In addition, microinjection of the SH2 domain into transformed fibroblasts partially restored a normal actin stress fiber pattern suggesting a stimulatory role of SH2B1 in normal and malignant cell proliferation (Riedel et al, 2000). These studies suggested that SH2B1 plays a fundamental role in receptor tyrosine kinase-mediated cellular functions and physiologic and pathologic activities of many cancers.…”

“…All the four isoforms of SH2B1 have been shown to be able to increase DNA synthesis and cellular proliferation stimulated by different levels of PDGF or IGF-I induced mitogenesis (Riedel et al, 2000;Yousaf et al, 2001), PDGF and IGF-I receptor are overexpression in the NSCLC tissues and cell lines (Soderdahl et al, 1988;Cosaceanu et al, 2005), they can promote the proliferation of tumor cells and the formation of new vessels, induce the tumor growth, local infiltration and transfer, also induce vasa lymphatica growth and promote lymph node metastases (Favoni et al, 1994;Koukourakis et al, 1997). SH2B1 β as a novel FGFR3 binding partner that mediates downstream biological effects of FGFR3 activation, increases the phosphorylation and nuclear translocation of STAT5B (Kong et al, 2002).…”

SH2B1 regulation of energy balance, body weight, and glucose metabolism

“…All four SH2B1 isoforms are able to increase the mitogenic response to epidermal growth factor, IGF-1, and PDGF-BB [14,69] . SH2B1 increases the ability of RET to promote transformation of NIH 3T3 cells [64] .…”

TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors

“…The use of cell penetrating peptides, like the HIV peptide TAT, has the advantage of avoiding this pathway and taking the cargo directly into the cell. TAT-mediated cytoplasmic uptake of drug conjugated polymers [9,10], plasmid DNA [10], bacteriophages [11], magnetic nanoparticles of about 10-20 nm in diameter [12] and even liposomes having a diameter of 200 nm [13] has been documented in the literature [14][15][16][17]. Until now the mechanism of internalization of TAT peptide is unclear.…”