Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis

Abstract

After internalization, transmembrane receptors (TMRs) are typically recycled back to the cell surface or targeted for degradation. Efficient TMR trafficking is critical for regulation of several processes, including signal transduction pathways, development, and disease. Here, we determined that trafficking of the angiogenic receptor neuropilin-1 (NRP-1) is abrogated by the liver kinase B1 (LKB1), a serine-threonine kinase of the calcium calmodulin family. We found that aberrant NRP-1 expression in tumor cells from patients with lung adenocarcinoma is associated with decreased levels of LKB1. In cultured lung cells, LKB1 accentuated formation of a complex between NRP-1 and RAB7 in late endosomes. LKB1 specifically bound GTP-bound RAB7, but not a dominant-negative GDP-bound form of RAB7, promoting rapid transfer and lysosome degradation of NRP-1. siRNA-mediated depletion of RAB7 disrupted the transfer of NRP-1 to the lysosome, resulting in recovery of the receptor as well as increased tumor growth and angiogenesis. Together, our findings indicate that LKB1 functions as a RAB7 effector and suppresses angiogenesis by promoting the cellular trafficking of NRP-1 from RAB7 vesicles to the lysosome for degradation. Furthermore, these data suggest that LKB1 and NRP-1 have potential as therapeutic targets for limiting tumorigenesis.