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Phosphorylation of the Unique C-terminal Tail of the Alpha Isoform of the Scaffold Protein SH2B1 Controls the Ability of SH2B1alpha to Enhance Nerve Growth Factor Function.
Molecular and Cellular Biology 2017 December 12
The scaffold protein SH2B1, a major regulator of body weight, is recruited to the receptors of multiple cytokines and growth factors, including nerve growth factor (NGF). The β isoform, but not the α isoform, of SH2B1 greatly enhances NGF-dependent neurite outgrowth of PC12 cells. Here we asked how the unique C-terminal tails of the α and β isoforms modulate SH2B1 function. We compared the actions of SH2B1α and SH2B1β to those of the N-terminal 631 amino acids shared by both isoforms. In contrast to the β-tail, the α-tail inhibited the ability of SH2B1 to both cycle through the nucleus and enhance NGF-mediated neurite outgrowth, gene expression, phosphorylation of Akt and PLCγ and autophosphorylation of the NGF receptor TrkA. These functions were restored when Tyr753 in the α-tail was mutated to phenylalanine. We provide evidence that TrkA phosphorylates Tyr753 in SH2B1α, as well as tyrosines 439 and 55 in both SH2B1α and SH2B1β. Finally, co-expression of SH2B1α, but not SH2B1α Y753F, inhibited the ability of SH2B1β to enhance neurite outgrowth. These results suggest that the C-terminal tails of SH2B1 isoforms are key determinants of the cellular role of SH2B1. Furthermore, the function of SH2B1α is regulated by phosphorylation of the α-tail.
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