Differential Roles of Grb2 and AP-2 in p38 MAPK- and EGF-Induced EGFR Internalization

TY - JOUR

T1 - Differential Roles of Grb2 and AP-2 in p38 MAPK- and EGF-Induced EGFR Internalization

AU - Grandal, Michael V

AU - Grøvdal, Lene M

AU - Henriksen, Lasse

AU - Andersen, Mette H

AU - Holst, Mikkel R

AU - Madshus, Inger H

AU - van Deurs, Bo

N1 - © 2011 John Wiley & Sons A/S.

PY - 2012/4

Y1 - 2012/4

N2 - The epidermal growth factor receptor (EGFR) is an important regulator of normal growth and differentiation, and it is involved in the pathogenesis of many cancers. Endocytic downregulation is central in terminating EGFR signaling after ligand stimulation. It has been shown that p38 MAPK activation also can induce EGFR endocytosis. This endocytosis lacks many of the characteristics of ligand-induced EGFR endocytosis. We compared the two types of endocytosis with regard to the requirements for proteins in the internalization machinery. Both types of endocytosis require clathrin, but while epidermal growth factor (EGF)-induced EGFR internalization also required Grb2, p38 MAPK-induced internalization did not. Interestingly, AP-2 knock down blocked p38 MAPK-induced EGFR internalization, but only mildly affected EGF-induced internalization. In line with this, simultaneously mutating two AP-2 interaction sites in EGFR affected p38 MAPK-induced internalization much more than EGF-induced EGFR internalization. Thus, it seems that EGFR in the two situations uses different sets of internalization mechanisms.

AB - The epidermal growth factor receptor (EGFR) is an important regulator of normal growth and differentiation, and it is involved in the pathogenesis of many cancers. Endocytic downregulation is central in terminating EGFR signaling after ligand stimulation. It has been shown that p38 MAPK activation also can induce EGFR endocytosis. This endocytosis lacks many of the characteristics of ligand-induced EGFR endocytosis. We compared the two types of endocytosis with regard to the requirements for proteins in the internalization machinery. Both types of endocytosis require clathrin, but while epidermal growth factor (EGF)-induced EGFR internalization also required Grb2, p38 MAPK-induced internalization did not. Interestingly, AP-2 knock down blocked p38 MAPK-induced EGFR internalization, but only mildly affected EGF-induced internalization. In line with this, simultaneously mutating two AP-2 interaction sites in EGFR affected p38 MAPK-induced internalization much more than EGF-induced EGFR internalization. Thus, it seems that EGFR in the two situations uses different sets of internalization mechanisms.

U2 - 10.1111/j.1600-0854.2011.01322.x

DO - 10.1111/j.1600-0854.2011.01322.x

M3 - Journal article

C2 - 22192528

SN - 1398-9219

VL - 13

SP - 576

EP - 585

JO - Traffic

JF - Traffic

IS - 4

ER -