Rabs and cancer cell motility

Abstract

The Rab family of small GTPases functions in regulating vesicular transport in all eukaryotes. In the past few years, several important reports have linked some members of the Rab family to intriguing mechanistic aspects of cancer cell migration and invasiveness. Rab5 and Rab21 associate with a-integrin subunits and modulate their endosomal traffic and subcellular localization. Expression of the latter enhances adhesion and migration of certain cancer cell types. Rab25 has been functionally linked to tumor progression and the invasiveness of some epithelial cancers. Rab25 promotes invasive migration of cells in three-dimensional microenvironments by associating with a5b1 integrin, and directing its recycling to dynamic ruffling protrusions at the migrating cell front. Acting directly, or through its effector, the Rab-coupling protein, Rab25 could potentially engage both integrin and epidermal growth factor receptor and enhance their oncogenic recycling and signaling. Tumor invasiveness may also be modulated by Rab8-mediated exocytic traffic of MT1-matrix metalloproteinase, with the latter's activity likely influenced by interaction with the mammalian suppressor of Sec4 (Mss4), a Rab8 guanine nucleotide exchange factor, and integrin. We discuss highlights in the recent literature that point towards a role for Rab-mediated membrane traffic in cancer cell migration and invasion. Cell Motil.

Important role of integrins in the cancer biology

“…α5β1 integrin is linked to the actin cytoskeleton through Tensin at focal adhesions; inhibition of ILK or PINCH blocks maturation of focal adhesions, which in turn destabilizes the linkages between α5β1 integrin and actin cytoskeleton [41]. Also, α5β1 integrin associates with Rab25 to promote invasion of cancer cells; thus, the association has been functionally linked to the progression of tumor invasiveness, particularly in some epithelial cancers [42] (Fig. 1).…”

Rab25 upregulation correlates with the proliferation, migration, and invasion of renal cell carcinoma

“…Recently, potential functions of Rab GTPases in various tumorrelated processes have been identified [9,11], and the importance of the intracellular-trafficking functions of Rab GTPases has been elucidated by demonstrating that these proteins coordinate the transformation between normal and cancerous cells [5]. Furthermore, Rabs have been shown to direct the cross-talk between cancerous cells and stromal cells and to be capable of creating a favorable environment for tumor growth, invasion, and migration [8e10].…”

Integrins

“…Induce invasion in prostate cancer [41], breast cancer [42,43], and epithelial cancer cells [44]; promote invasion and metastasis of ovarian cancer [45]; promote migration, proliferation, and metastasis in experimental lung cancer [46]; induce migration and invasion of murine melanoma [47]; promote angiogenesis and lymph node metastasis in cervical cancer [48] αvβ3…”