LKB1 in transmembrane receptor signaling

Signal processing and integration is critical in physiology, as it is in disease conditions. Conversion of extracellular signals into appropriate biological responses by cell membrane receptors, and subsequent extinction of signaling events is critical to cellular hemostasis. Defective trafficking, internalization or degrardation of transmembrane receptors (TMRs) result in perturbed activation of signaling networks, which play essential roles in disease initiation or accentuation. In our recent study, we found that liver kinase B1 (LKB1), a calcium-calmodulin family member abrogated neuropilin-1 (NRP-1) protein in lung cancer clinical specimens and cell lines [1]. Surprisingly, this observation was reminiscent to our previous finding in which LKB1 attenuated the activation of a repertoire of receptor tyrosine kinases (RTKs), including EGFR, ErbB2, HGFR (c-Met) and EphA2 [2]. The regulation of TMRs by LKB1 appears to be a recurring pattern in cancer cells but occur via different mechanisms. Unlike LKB1-mediated dephosphorylation of RTKs via accentuation of selected phosphatase activity, NRP-1 attenuation was promoted by LKB1-RAB7 GTPase complex [1, 2]. We demonstrated for the first time that LKB1 is a RAB7 effector and suppresses tumor angiogenesis by promoting cellular trafficking of NRP-1 from RAB7 vesicles to the lysosome for degradation. LKB1 specifically bound active GTP-Q67L RAB7 construct, but not the dominant-negative GDP-T22N form. NRP-1 localization within RAB7, a late endocytic target was not detected in early (RAB5) or recycling (RAB11) endosomal markers [1]. With over 60 different mammalian RAB family-members, the selectivity may be context-dependent, and the relationship between LKB1 and RAB family-members requires further investigation. Our findings indicated that hypoxia, a property of tumor micro-environment promotes LKB1 nuclear export to the cytosol, where it interacts with NRP-1 and RAB7 [1]. LKB1 expression was consistent with its tumor suppression functions, which included inhibition of angiogenesis and tumor growth in vivo. Conversely, loss of LKB1 exacerbated tumor-enhancing phenotypes [1]. We have recently observed a similar inverse expression profile between LKB1 and NRP-1 proteins within endometrial cancer specimens. We found that NRP-1 positively correlated with NEDD9 pro-metastatic protein. As expected, LKB1 abrogation of NRP-1 protein correlated with decreased metastatic potential of cancer cells in vitro (unpublished observations). In contrast to well-established RTKs, such as EGFR that have been studied for decades, several NRP-1 functions remain relatively unknown. NRP-1 is a non-tyrosine kinase, type-I transmembrane receptor that is largely associated with the VEGF receptor family. Canonical NRP-1 functions in tumor angiogenesis is strongly linked to VEGFR2. In our studies, NRP-1-mediated tumor …