SOCS2 Induces Neurite Outgrowth by Regulation of Epidermal Growth Factor Receptor Activation

Abstract

Suppressor of cytokine signaling (SOCS) 2 is a negative regulator of growth hormone (GH) signaling that regulates body growth postnatally and neuronal differentiation during development. SOCS2 binds to the GH receptor and inhibits GH signaling, including attenuation of STAT5 activation. Here we describe a new function and mechanism of action for SOCS2. Overexpression of SOCS2 in central nervous system neurons promoted neurite outgrowth, and in PC12 cells, neurite outgrowth was induced under nondifferentiating conditions, leading to inhibition of the neurite-inhibitory GTPase Rho and activation of the neurite-promoting GTPase Rac1. Addition of the epidermal growth factor receptor (EGFR) inhibitors PP3 or AG490 or the Src kinase inhibitor PP2 blocked the SOCS2-induced neurite outgrowth. The overexpressed SOCS2 bound to the EGFR, which was constitutively phosphorylated at Tyr 845 , the Src binding site. Overexpression of the phosphatase SHP-2 reduced the constitutive EGFR phosphorylation and subsequent neurite outgrowth. SOCS2 expression also resulted in a modest 30% decrease in phosphorylation of STAT5b at Tyr 699 , which is the primary site on STAT5 phosphorylated by GH; however, total tyrosine phosphorylation of STAT5 was decreased by 75-80% under basal and epidermal growth factorstimulated conditions. Our findings suggest that SOCS2 regulates EGFR phosphorylation, leading to regulation of neurite outgrowth through a novel pathway that is distinct from GH.

SOCS proteins in regulation of receptor tyrosine kinase signaling

“…Furthermore, SOCS2 associates with tyrosine phosphorylated EGFR and probably competes with SRC for binding to the same binding site, pY845, in the EGFR and inhibits EGF-induced STAT5 phosphorylation [48]. Thus SOCS2 might regulate EGFR signaling by two parallel mechanisms, both by destabilizing EGFR and by competing with SRC for binding to the receptor.…”

Regulation of Basal and Injury-Induced Fate Decisions of Adult Neural Precursor Cells: Focus on SOCS2 and Related Signalling Pathways

“…Important for SOCS2 interaction, EGF also activates STAT5, a process involving the Src tyrosine kinase [185][186][187]. Overexpression of SOCS2 in PC12 cells inhibited this EGF induced STAT5 phosphorylation [176]. The EGFR was also constitutively phosphorylated at the Src binding site, Tyr…”

“…Additionally, PC12 cells and neural cells from SOCS2Tg mice demonstrate increased neurite outgrowth in tissue culture [171,[174][175][176]. GH is an inhibitor of neural differentiation and its negative regulation by SOCS2 is evident by the reduction in neuronal differentiation in neural stem cell cultures of SOCS2 -/-mice [171,174].…”

“…SOCS2 can also regulate signalling via the EGF receptor (EGFR) [175,176]. The main physiological target for EGFR is EGF.…”

Gold nanoparticle-based beacon to detect STAT5b mRNA expression in living cells: a case optimized by bioinformatics screen

“…Here, STAT5b expression-positive HepG-2 and STAT5b expression-negative PC12 cell lines were used as testing and control groups, respectively. 18,33,34 Qualitative assessment was performed by CLSM imaging (Figure 3). As shown, after treatment with the hDAuNP beacon, HepG-2 cells all displayed a strong fluorescent signal, while PC12 cells did not exhibit any obvious fluorescent signal.…”