SOCS2 induces neurite outgrowth by regulation of epidermal growth factor receptor activation.
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 Tyr845, 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 Tyr699, 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 factor-stimulated conditions. Our findings suggest that SOCS2 regulates EGFR phosphorylation, leading to regulation of neurite outgrowth through a novel pathway that is distinct from GH.
Goldshmit
Yona
Y
Neural Regeneration Laboratory, Centre for Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia.
Walters
Claire E
CE
Scott
Hannah J
HJ
Greenhalgh
Christopher J
CJ
Turnley
Ann M
AM
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology*; D013006:Growth Hormone / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D016501:Neurites / Q000502:physiology / Q000648:ultrastructure; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D016716:PC12 Cells; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C491408:Socs2 protein, rat; C494097:Stat5b protein, rat; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D013006:Growth Hormone; D066246:ErbB Receptors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat