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

Abstract

BackgroundGrowth 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?ResultsOur 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 Ins2Akita mouse retinas. Decreased retinal IR activation has previously been reported in this mouse line.ConclusionsOur results suggest that phosphorylation status of the BPS region of Grb14 determines the positive or negative role it will play in IR signaling.

Activation of oncogenic tyrosine kinase signaling promotes insulin receptor-mediated cone photoreceptor survival

“…We previously reported that the SH2-domain of vSrc interacts with phosphorylated Grb14 in vitro [23]. We used this probe to determine the in vivo phosphorylation of Grb14 in cone-dominant retina.…”

“…The PTP1B dephosphorylates IR, and the un-phosphorylated form of Grb14 inactivates IR by direct binding to the catalytic loop of the IR; consequently, the IR becomes inactive [20, 21]. In light, the IR overcomes the inactivation by PTP1B and Grb14 through photobleaching of rhodopsin, which activates a non-receptor tyrosine kinase, Src [22, 23], that phosphorylates Grb14. The phosphorylated Grb14 acts a competitive inhibitor of PTP1B and inhibits its activity [22], and protects the IR from dephosphorylation [23].…”

“…In light, the IR overcomes the inactivation by PTP1B and Grb14 through photobleaching of rhodopsin, which activates a non-receptor tyrosine kinase, Src [22, 23], that phosphorylates Grb14. The phosphorylated Grb14 acts a competitive inhibitor of PTP1B and inhibits its activity [22], and protects the IR from dephosphorylation [23]. The activated form of IR regulates the neuroprotective downstream effector cascade.…”

Type 2 Diabetes Mellitus and Protein-Tyrosine Phosphatase 1B1

“…Insulin binding alpha subunits of the receptor induced phosphorylation of tyrosine residues and protein tyrosine kinase (PTK) of beta subunits, and resulted in a series of phosphorylation and dephosphorylation cascade reactions including mitogen-activated protein kinases (MAPK) and PI3K/Akt signal pathways to regulate metabolism. Whereas, when the concentration of insulin is beyond the physiological concentration (hyperinsulinemia), insulin promoted cell proliferation and developments, which may due to the combination of insulin with insulin-like growth factor 1 receptor (IGF-1R) or insulin-like growth factor 1 (IGF-1) hybrid insulin receptor, and had nothing with insulin receptor [13].…”

“…Insulin binding alpha subunits of the receptor induced phosphorylation of tyrosine residues and protein tyrosine kinase (PTK) of beta subunits, and resulted in a series of phosphorylation and dephosphorylation cascade reactions including mitogen-activated protein kinases (MAPK) and PI3K/Akt signal pathways to regulate metabolism. Whereas, when the concentration of insulin is beyond the physiological concentration (hyperinsulinemia), insulin promoted cell proliferation and developments, which may due to the combination of insulin with insulin-like growth factor 1 receptor (IGF-1R) or insulin-like growth factor 1 (IGF-1) hybrid insulin receptor, and had nothing with insulin receptor [13].Many reports indicate that PTP1B is an established metabolic regulation in mammals and a pharmacological target for type 2 diabetes. During the combination of insulin and its receptor, PTP1B could catalyze insulin receptor (IR) and insulin receptor substrates (IRS) de phosphorylation, coordinated the balance between phosphorylation and de phosphorylation of tyrosine residues, which resulted in downregulation of insulin signal transduction [14].…”