New mechanism for increased levels of metastatic chemokine receptors revealed
Thomas Slagsvold, a postdoctoral fellow in Harald Stenmarks group, has recently published in EMBO Journal (impact factor 10,053) a paper that sheds light on how the cellular levels of the chemokine receptor CXCR4 are increased in cancers. This issue is of considerable interest because enhanced expression of CXCR4 has been strongly associated with metastasis of breast cancer cells to lung tissue.
Recent studies by others had shown that HER2, a member of the epidermal growth factor receptor family that strongly increases the aggressiveness of breast tumours, causes increased cellular CXCR4 levels by stimulating PI 3-kinase, an enzyme that phosphorylates a specific phospholipid to yield the lipid product known as PIP3. A collaborative project between Stenmarks group and Adriano Marchese, a CXCR4 expert at the Loyola University of Chicago, had previously revealed that the ubiquitin ligase AIP4 is crucial for the degradation of CXCR4 by ubiquitinating the receptor and thus targeting it for degradation in lysosomes (Marchese et al., Dev.Cell 2003). In the present EMBO Journal paper, Slagsvold and co-workers collaborated with Marchese to show that a protein kinase activated by PIP3, PDK1, activates another protein kinase, CISK. CISK in turn regulates AIP4 through phosphorylation of specific residues and thus prevents targeting of CXCR4 to the degradative lysosomes. This is likely to be part of the reason why CXCR4 levels are increased in HER2-overexpressing tumours and might provide a novel therapeutic target.
Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, Agrewala JN, Agrotis A, Aguilar PV, Ahmad ST, Ahmed ZMet al.(2021) Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) Autophagy, 1-382(in press) DOI 10.1080/15548627.2020.1797280, PubMed 33634751
Schultz SW, Agudo-Canalejo J, Chino H, Migliano SM, Saito C, Koyama-Honda I, Stenmark H, Brech A, Mizushima N, Knorr RL, May AI(2021) Should I bend or should I grow: the mechanisms of droplet-mediated autophagosome formation Autophagy, 1-3(in press) DOI 10.1080/15548627.2021.1887548, PubMed 33629888
Agudo-Canalejo J, Schultz SW, Chino H, Migliano SM, Saito C, Koyama-Honda I, Stenmark H, Brech A, May AI, Mizushima N, Knorr RL(2021) Wetting regulates autophagy of phase-separated compartments and the cytosol Nature DOI 10.1038/s41586-020-2992-3, PubMed 33473217