It Takes a CAML to Get Back to the Surface

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Science's STKE  19 Aug 2003:
Vol. 2003, Issue 196, pp. tw325-TW325
DOI: 10.1126/stke.2003.196.tw325

Receptor tyrosine kinases, such as the epidermal growth factor (EGF) receptor, are activated at the cell surface upon ligand binding, but are then rapidly internalized and destined for one of two fates--degradation or recycling back to the cell surface. Delivery to the lysosome for destruction involves ubiquitination of receptors by c-Cbl, and then delivery to multivesicular bodies by ESCRT-1 (endosomal sorting complex required for transport-1). Less is understood about factors that control shuttling of cargo to the recycling endosome. Tran et al. have determined that a protein called CAML (calcium-modulating cyclophilin ligand) is required for efficient EGF receptor recycling. CAML is a putative membrane protein of the endoplasmic reticulum (ER) and is thought to promote calcium signaling. Epithelial-like cells lacking CAML were derived from stem cells of CAML-null mouse embryos. The absence of CAML impaired the cellular mitogenic response to EGF. However, these cells had an increased total amount of EGF receptor, although not at the cell surface. Rather, increased cytoplasmic accumulation of the EGFR was observed, a result of a decreased recycling rate and not of decreased receptor degradation. The CAML-null cells showed normal initial EGF-induced down-regulation of receptor from the cell surface, indicating that CAML is not required for receptor-ligand binding and endocytosis. Interaction between endogenous EGF receptor and CAML was detected by immunoprecipitation from cell lysates as well as by colocalization within cells, and the association depended on treatment of cells with EGF. CAML also associated with EGF receptor that did not appear to be ubiquitinated or tyrosine-phosphorylated. It is known that EGF receptor that is destined to be recycled is dephosphorylated by a protein phosphatase called PTP1B in the ER. The authors propose that CAML could then bind the EGF receptor and deliver it to the recycling endosome.

D. D. Tran, H. R. Russell, S. L. Sutor, J. van Deursen, R. J. Bram, CAML is required for efficient EGF receptor recycling. Dev. Cell 5, 245-256 (2003). [Online Journal]

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