Anks1a regulates COPII-mediated anterograde transport of receptor tyrosine kinases critical for tumorigenesis.
ErbB2 signalling, which is amplified by EphA2 binding, is an important therapeutic target for breast cancer. Despite the importance of the EphA2/ErbB2 complex in promoting breast tumorigenesis, the mechanism by which these receptor tyrosine kinases (RTKs) are exported from the endoplasmic reticulum (ER) remains poorly understood. Here we report that the PTB adaptor Anks1a is specifically localized to the ER on its own serine phosphorylation. Once there, Anks1a acts as an important regulator of COPII-mediated EphA2 ER export. The Anks1a ankyrin repeat domain binds EphA2 and causes it to accumulate at sites of ER exit. Simultaneously, the Anks1a PTB domain binds Sec23. This induces internalization of EphA2 via COPII vesicles, while Anks1a remains behind on the ER membrane. EphA2 also binds ErbB2 in the ER and seems to load ErbB2 into growing COPII carriers. Together, our study reveals a novel mechanism that regulates the loading of RTKs into COPII vesicles.
Department of Biological Science, Sookmyung Women's University, Chungpa-ro 47gil 100, Yongsan-gu, Seoul 140-742, Korea.
Haeryung
http://orcid.org/0000-0002-1539-9259
H
Lee
Department of Biological Science, Sookmyung Women's University, Chungpa-ro 47gil 100, Yongsan-gu, Seoul 140-742, Korea.
Hyuna
H
Noh
Department of Biomedical Laboratory Science, College of Health Science, Eulji University, Seongnam-Si, Gyeonggi-Do 13135, Korea.
Jiyoung
J
Mun
Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Changkyu
C
Gu
Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Sanja
S
Sever
Department of Biological Science, Sookmyung Women's University, Chungpa-ro 47gil 100, Yongsan-gu, Seoul 140-742, Korea.
Soochul
S
Park
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D022181:COP-Coated Vesicles / Q000502:physiology*; D063646:Carcinogenesis; D002352:Carrier Proteins; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
C557872:ANKS1A protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C498028:Odin protein, mouse; D020794:Receptor Protein-Tyrosine Kinases