A novel TIP30 protein complex regulates EGF receptor signaling and endocytic degradation.
Activated epidermal growth factor receptor (EGFR) continues to signal in the early endosome, but how this signaling process is regulated is less well understood. Here we describe a protein complex consisting of TIP30, endophilin B1, and acyl-CoA synthetase long chain family member 4 (ACSL4) that interacts with Rab5a and regulates EGFR endocytosis and signaling. These proteins are required for the proper endocytic trafficking of EGF-EGFR. Knockdown of TIP30, ACSL4, endophilin B1, or Rab5a in human liver cancer cells or genetic knock-out of Tip30 in mouse primary hepatocytes results in the trapping of EGF-EGFR complexes in early endosomes, leading to delayed EGFR degradation and prolonged EGFR signaling. Furthermore, we show that Rab5a colocalizes with vacuolar (H(+))-ATPases (V-ATPases) on transport vesicles. The TIP30 complex facilitates trafficking of Rab5a and V-ATPases to EEA1-positive endosomes in response to EGF. Together, these results suggest that this TIP30 complex regulates EGFR endocytosis by facilitating the transport of V-ATPases from trans-Golgi network to early endosomes.
Department of Biomedical and Integrative Physiology, Michigan State University, East Lansing, Michigan 48824, USA.
Chengliang
C
Zhang
Aimin
A
Li
Xinchun
X
Zhang
Hua
H
Xiao
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D009097:Multienzyme Complexes; D012097:Repressor Proteins; C525546:Tip30 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000217:Acyltransferases; D000123:Acetyltransferases; C111246:HTATIP2 protein, human; C018764:2-acylglycerophosphate acyltransferase; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D020696:rab5 GTP-Binding Proteins; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
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