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.
Palomo-Guerrero M, Fadó R, Casas M, Pérez-Montero M, Baena M, Helmer PO, Domínguez JL, Roig A, Serra D, Hayen H, Stenmark H, Raiborg C, Casals N(2019) Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth Elife, 8 DOI 10.7554/eLife.51063, PubMed 31868590
Fang EF, Hou Y, Lautrup S, Jensen MB, Yang B, SenGupta T, Caponio D, Khezri R, Demarest TG, Aman Y, Figueroa D, Morevati M, Lee HJ, Kato H, Kassahun H, Lee JH, Filippelli D, Okur MN, Mangerich A, Croteau DL, Maezawa Y, Lyssiotis CA, Tao J, Yokote K, Rusten TEet al.(2019) NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome Nat Commun, 10(1), 5284 DOI 10.1038/s41467-019-13172-8, PubMed 31754102