IRS1/2 säätelevät myös aktivoidun IR:n endosytoosia . Mitoosikontrollitekijöiden osuus (2019)

https://ww1/2 w.ncbi.nlm.nih.gov/pubmed/30931927

Nat Commun. 2019 Apr 1;10(1):1473. doi: 10.1038/s41467-019-09318-3.

Mitotic regulators and the SHP2-MAPK pathway promote IR endocytosis and feedback regulation of insulin signaling.

Choi E¹, Kikuchi S¹, Gao H¹, Brodzik K¹, Nassour I², Yopp A², Singal AG², Zhu H², Yu H³.

Abstract

Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.

PMID:

30931927

PMCID:

PMC6443781

DOI:

10.1038/s41467-019-09318-3

[Indexed for MEDLINE]

Free PMC Article

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Introduction

The pancreatic hormone insulin controls glucose homeostasis and promotes cell growth and proliferation. Dysregulation of insulin signaling is linked to human metabolic syndromes and cancer¹. Insulin binds to the insulin receptor (IR) on the plasma membrane (PM), and triggers phosphorylation-mediated activation of crucial enzymes that regulate glucose and lipid metabolism, and cell growth and division^2,3. Activated IR phosphorylates itself and the IR substrate (IRS) proteins on tyrosines.
Phosphorylated IRS proteins bind to multiple downstream effectors and adaptors, and activate two major branches of insulin signaling: the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways.
 The PI3K-AKT pathway mainly governs metabolic homeostasis, (Vertaa IRB!)
whereas the MAPK pathway controls cell growth and proliferation. (Vertaa. IRA!)

 Src homology phosphatase 2 (SHP2, also known as PTPN11) binds to the C-terminal phosphotyrosine sites of IRS1/2 and promotes the activation of the MAPK pathway^4,5.

 Mutations of IR cause severe inherited insulin resistance syndromes⁶, but the molecular mechanisms underlying insulin resistance in type 2 diabetes are complex and multifactorial¹. One common theme is that insulin resistance in diabetic animals or patients causes ectopic accumulation of diacylglycerol and abnormal activation of novel protein kinase Cs, which suppress insulin signaling at the level of IRS1 and possibly IR^1,7.

The spindle checkpoint monitors kinetochore-microtubule attachment during mitosis and prevents chromosome missegregation^8,9.

 In response to unattached kinetochores, the mitosis arrest deficiency 2 (MAD2) and budding uninhibited by benomyl 1-related 1 (BUBR1) proteins, as subunits of the mitotic checkpoint complex (MCC), inhibit the anaphase-promoting complex APC/cyclosome bound to its mitotic activator, the cell division cycle 20 (CDC20) protein, to delay chromosome segregation^10,11,12,13.

When all kinetochores are properly attached by microtubules, the MAD2-binding protein p31^comet (also called MAD2L1BP) prevents the conformational activation of MAD2 and collaborates with the ATPase TRIP13 to disassemble MCC, thus promoting chromosome segregation^{11,14,15,16,17}.

We have recently discovered a critical role of MAD2, BUBR1, and p31^comet in insulin signaling during interphase (Fig. 1a)^18,19. MAD2 and BUBR1 are required for clathrin-mediated endocytosis of IR. MAD2 directly binds to the C-terminal MAD2-interacting motif (MIM) of IR, and recruits the clathrin adaptor AP2 to IR through BUBR1.

p31^comet prevents spontaneous IR endocytosis through blocking the interaction of BUBR1-AP2 with IR-bound MAD2. Adult liver-specific p31^comet knockout (KO) mice exhibit premature IR endocytosis in the liver and whole-body insulin resistance.

Conversely, BUBR1 deficiency delays IR endocytosis and enhances insulin sensitivity in mice. These findings implicate dysregulation of IR endocytosis as a potential mechanism of insulin resistance.

Fig. 1