[No authors listed]
Calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 2 (RAMP2) comprise a receptor for adrenomedullin (AM). Although it is known that AM induces internalization of CLRâ¢RAMP2, little is known about the molecular mechanisms that regulate the trafficking of CLRâ¢RAMP2. Using HEK and HMEC-1 cells, we observed that AM-induced activation of CLRâ¢RAMP2 promoted ubiquitination of CLR. A mutant (CLRÎ9KR), lacking all intracellular lysine residues was functional and trafficked similar to the wild-type receptor, but was not ubiquitinated. Degradation of CLRâ¢RAMP2 and CLRÎ9KRâ¢RAMP2 was not dependent on the duration of AM stimulation or ubiquitination and occurred via a mechanism that was partially prevented by peptidase inhibitors. Degradation of CLRâ¢RAMP2 was sensitive to overexpression of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), but not to HRS knockdown, whereas CLRÎ9KRâ¢RAMP2 degradation was unaffected. Overexpression, but not knockdown of HRS, promoted hyperubiquitination of CLR under basal conditions. Thus, we propose a role for ubiquitin and HRS in the regulation of AM-induced degradation of CLRâ¢RAMP2.
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