Insulin receptor trafficking steers insulin action.

摘要: In this issue, Boothe and colleagues analyze insulin receptor trafficking in pancreatic beta cells to unravel the route of receptors provide novel insights into potentially different roles splice variants [1]. Glucose dependent release from is under tight control various nutritional, hormonal nervous inputs. Among signaling cascades modulating cell function, autocrine activation regulates both synthesis release, loss results type 2 diabetes mice [2]. However, analysis action complicated by continuous fluctuations local concentrations presence proinsulin as a low affinity ligand. Binding induces at membrane and, upon internalization, endosome. The magnitude kinetics internalization depend on extracellular co-factors, well amplitude [3]. Insulin required turn off signaling, but it endosome specific signal transduction, complexes differ compared those Nevertheless, whether or plays beneficial detrimental role for function survival remains controversial [4]. To investigate cells, developed overexpression constructs A B that were tagged with pH-resistant fluorescent proteins. contrast previous C-terminally constructs, authors introduced fluorescence tags extracellularly, between furin-cleavage site transmembrane domain. Compared surface localization receptors, inter-domain predominantly localized intracellular vesicles, co-localizing endogenous these cells. Hence, data indicate regular culture conditions, vast majority are within vesicles. It will be interesting see if can also observed other how non-insulin producing changes hyperinsulinemia, resistance diabetes. Further exploring phenomenon, demonstrate undergo caveolin-1 mediated endocytosis subsequent flotillin-1 positive structures degradation lysosomes. Thus, current study indicates bypasses classical clathrin Rab5a or Rab7 pathway These line primary adipocytes showing caveolae, caveolae-dependent [5]. did not reveal differences receptor-A receptor-B studies analyzing hepatocytes liver, autophosphorylation followed rapid via clathrin-coated vesicles [6]. Boothe report internalized activate Erk caveolin-dependent manner, whereas Akt unaffected. Interestingly, R252C mutation human receptor, which causes severe resistance, links selective reduction reduced ligand binding [7]. could suggest selectively reduces Shc endosome. In context action, generally more associated proliferation than through Akt. tempting speculate that, least part, long sought-after mitogenic versus metabolic spatial (cell endosome) distribution regulated affinities. Evidence differential outcome, depending availability intensity/duration, comes Jimenez-Feltstrom colleagues, who showed have stimulatory effect secretion, while high result inhibition [8]. Furthermore, we previously described proteoglycan glypican-4 an modulator [9], suggesting IGF1R integrated network regulatory proteins, thereby establishing subcellular distribution. Thus, would similarities signaling. no final conclusion require detailed analysis, forms heterodimers isoforms, though affinities insulin, complicating analysis. using combination transgenic mouse lines new imaging tools allow dissecting temporal receptor/IGF1R action. The et al. offers regulation opening up research opportunities. Recently, clathrin-dependent epidermal growth factor (EGFR) was shown recycling clathrin-independent leads EGFR [10]. Since reports there indeed back plasma membrane, Hela cells. Future need integrate its further understand complex action. Moreover, alterations only influence transduction surface, alter endosome, contributing impaired promoting pathogenesis.