Platelet-derived growth factor receptor-mediated signal transduction from endosomes.
Although accumulated evidence supports the concept of endosomal signaling of receptor tyrosine kinases, most results are generated from studies of epidermal growth factor receptor (EGFR). It is not clear whether the concept of endosomal signaling could be generally applied to the other receptor tyrosine kinases. For example, platelet-derived growth factor receptor (PDGFR) is very similar to EGFR in terms of both signaling and trafficking; however, little is known about the endosomal signaling of PDGFR. In this research, we applied the same approaches from our recent studies regarding EGFR endosomal signaling to investigate the endosomal signaling of PDGFR. We showed in this communication that we are able to establish a system that allows the specific activation of endosome-associated PDGFR without the activation of the plasma membrane-associated PDGFR and without disrupting the overall endocytosis pathway. By using this system, we showed that endosomal activation of PDGFR recruits various signaling proteins including Grb2, SHC, phospholipase C-gamma1, and the p85alpha subunit of phosphatidylinositol 3-kinase into endosomes and forms signaling complexes with PDGFR. We also showed that endosomal PDGFR signaling is sufficient to activate the major signaling pathways implicated in cell proliferation and survival. Moreover, we demonstrate that endosomal PDGFR signaling is sufficient to generate physiological output including cell proliferation and cell survival.
Wang
Yi
Y
Department of Cell Biology and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Pennock
Steven D
SD
Chen
Xinmei
X
Kazlauskas
Andrius
A
Wang
Zhixiang
Z
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D017667:Adipocytes; D000818:Animals; D006528:Carcinoma, Hepatocellular; D002455:Cell Division; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D011992:Endosomes / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051380:GRB2 Adaptor Protein; D006801:Humans; D008113:Liver Neoplasms; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D011506:Proteins / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D011506:Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D010738:Type C Phospholipases; D051966:Phospholipase C gamma