The role of endocytic Rab GTPases in regulation of growth factor signaling and the migration and invasion of tumor cells

Abstract

Metastasis is characterized pathologically by uncontrolled cell invasion, proliferation, migration and angiogenesis. It is a multistep process that encompasses the modulation of membrane permeability and invasion, cell spreading, cell migration and proliferation of the extracellular matrix, increase in cell adhesion molecules and interaction, decrease in cell attachment and induced survival signals and propagation of nutrient supplies (blood vessels). In cancer, a solid tumor cannot expand and spread without a series of synchronized events. Changes in cell adhesion receptor molecules (e.g., integrins, cadherin-catenins) and protease expressions have been linked to tumor invasion and metastasis. It has also been determined that ligand-growth factor receptor interactions have been associated with cancer development and metastasis via the endocytic pathway. Specifically, growth factors, which include IGF-1 and IGF-2 therapy, have been associated with most if not all of the features of metastasis. In this review, we will revisit some of the key findings on perhaps one of the most important hallmarks of cancer metastasis: cell migration and cell invasion and the role of the endocytic pathway in mediating this phenomenon

<p>PVT1 Promotes the Proliferation and Migration of Non-Small Cell Lung Cancer via Regulating miR-148/RAB34 Signal Axis</p>

“…27 Rab proteins regulate cancer cell migration and invasion through modulating surface protein internalization, degradation, and recycling. 28,29 RAB34 leads to poor prognosis in high-grade glioma patients 18 which was overexpressed in HCC and may become a biomarker and therapeutic target for HCC. 30 Previous results uncovered the role of Rab34 in migration and invasion of breast cancer cells and its involvement in cancer metastasis.…”

AGAP2: Modulating TGFβ1-Signaling in the Regulation of Liver Fibrosis

“…Increasing evidence suggests that the activation of Ras proteins serves as a non-canonical intracellular signal transduction pathway for TGFβ1 [44]. The small-GTPases of the Ras family including Rab, Ran and Rho GTPases are key components in the regulation of TGFβ1 signaling during TGFβ1 receptor endocytosis, Smad trafficking and cross-talk with the actin cytoskeleton, respectively [45][46][47]. A recent review describes the cross-talk between Rho proteins and the TGFβ1 signaling pathway and their implication for the pathogenesis of human diseases as fibrosis [48], and Ren et al [49] describe how endostatin inhibits TGFβ-induced fibrosis in HSC by modulating the RhoA/ROCK signal pathway.…”

“…The stimulatory effect of AGAP2 on TGFβ1-induced HSC migration could involve different molecular mechanisms. In this sense, AGAP2 has been recently described as an Arf GAP which regulates integrin adhesion complexes by binding to and regulating focal adhesion kinase (FAK) [45,65]. This protein was named based on its prominent localization in the focal adhesions [73], cellular structures that connect actin cytoskeleton with the ECM formed by: 1) signaling proteins such as FAK, paxillin, and c-Src; and 2) structural proteins as talin and vinculin [74].…”

Concurrent depletion of Vps37 proteins evokes ESCRT-I destabilization and profound cellular stress responses

“…Some mechanisms for tumor cell-specific changes in the activity of endocytic machinery components that affect intracellular signaling have been already identified (Barbieri et al, 2016;Di Fiore and von Zastrow, 2014;Mellman and Yarden, 2013). For instance, many tumors exhibit deregulated expression of the ubiquitination machinery and small GTPases that control the rate of receptor degradation and recycling, respectively (Porther and Barbieri, 2015). However, despite the abundance of publicly available data, such as those deposited in The Cancer Genome Atlas [TCGA] (Weinstein et al, 2013), little has been done to systematically analyze the expression of receptor trafficking regulators in tumors and across tumor stages.…”