Spatial and temporal aspects and the interplay of Grb14 and protein tyrosine phosphatase-1B on the insulin receptor phosphorylation

Raju V. S. Rajala, Devaraj K. Basavarajappa, Radhika Dighe, Ammaji Rajala

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Growth factor receptor-bound protein 14 (Grb14) is an adapter protein implicated in receptor tyrosine kinase signaling. Grb14 knockout studies highlight both the positive and negative roles of Grb14 in receptor tyrosine kinase signaling, in a tissue specific manner. Retinal cells are post-mitotic tissue, and insulin receptor (IR) activation is essential for retinal neuron survival. Retinal cells express protein tyrosine phosphatase-1B (PTP1B), which dephosphorylates IR and Grb14, a pseudosubstrate inhibitor of IR. This project asks the following major question: in retinal neurons, how does the IR overcome inactivation by PTP1B and Grb14?. Results: Our previous studies suggest that ablation of Grb14 results in decreased IR activation, due to increased PTP1B activity. Our research propounds that phosphorylation in the BPS region of Grb14 inhibits PTP1B activity, thereby promoting IR activation. We propose a model in which phosphorylation of the BPS region of Grb14 is the key element in promoting IR activation, and failure to undergo phosphorylation on Grb14 leads to both PTP1B and Grb14 exerting their negative roles in IR. Consistent with this hypothesis, we found decreased phosphorylation of Grb14 in diabetic type 1 Ins2§ssup§Akita§esup§ mouse retinas. Decreased retinal IR activation has previously been reported in this mouse line. Conclusions: Our results suggest that phosphorylation status of the BPS region of Grb14 determines the positive or negative role it will play in IR signaling.

Original languageEnglish
Article number96
Pages (from-to)1-11
Number of pages11
JournalCell Communication and Signaling
Volume11
Issue number1
DOIs
Publication statusPublished - 18 Dec 2013
Externally publishedYes

Keywords

  • Grb14
  • Insulin receptor
  • PTP1B
  • Shp2
  • SRC activation
  • Tyrosine kinase signaling
  • Tyrosine phosphorylation

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