The Many Faces of Rap1 GTPase

Abstract

This review addresses the issue of the numerous roles played by Rap1 GTPase (guanosine triphosphatase) in different cell types, in terms of both physiology and pathology. It is one among a myriad of small G proteins with endogenous GTP-hydrolyzing activity that is considerably stimulated by posttranslational modifications (geranylgeranylation) or guanine nucleotide exchange factors (GEFs), and inhibited by GTPase-activating proteins (GAPs). Rap1 is a ubiquitous protein that plays an essential role in the control of metabolic processes, such as signal transduction from plasma membrane receptors, cytoskeleton rearrangements necessary for cell division, intracellular and substratum adhesion, as well as cell motility, which is needed for extravasation or fusion. We present several examples of how Rap1 affects cells and organs, pointing to possible molecular manipulations that could have application in the therapy of several diseases.

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

“…Rap1 has also been linked to bone growth, including in bovine chondrocyte models [224]. Rap1 has been identified to undergo post-translational modifications by phosphorylation, geranylgeranylation or guanine nucleotide exchange factors [225], but deimination in this pathway has not been identified before, to our knowledge. To what extent deimination contributes to the multifaceted functions of Rap1 signalling in health and disease may therefore be of considerable interest.…”

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

“…It is known for instance that stimulated MAC-1 orchestrates migration of polymorphonuclear granulocytes (PMN) in a MAPK-dependent manner, whereas activated LFA-1 induces phosphoinositide 3-kinase (PI3K)-dependent cell motility [26]. As outlined below, LFA-1-dependent cell migration depends on the small GTPase Rap-1 which mediates inside-out signaling [27].…”

“…AP-1 is also a transcription factor and regulates differentiation, proliferation and apoptosis of the cell [43]. Chemokine-triggered β2 integrin activation can transduce signaling over small GTPases, Rap [27] and/or Rho (Ras homolog gene) [39], Rac-1 (Ras-related C3 botulinum toxin substrate 1) [44], Cdc42 (Cell division control protein 42 homolog) [45], according Rho-GEF such as, CALDAG-GEF [46], DOCK2 (Dedicator of cytokinesis 2) [47], VAV1 (Vav Guanine Nucleotide Exchange Factor 1) [48], kinases, including STK4 (Serine/threonine-protein kinase 4) and SKAP55 (Src kinase-associated phosphoprotein 5) [49], and other signaling proteins like PLD1 (Phospholipase D1) [50] and adaptor proteins as ADAP (Adhesion and degranulation-promoting adaptor protein) [49] and PIP5K1C (Phosphatidylinositol-4-Phosphate 5-Kinase Type 1 Gamma) [51,52]. Altogether, inside-out signaling induces a conformational change of the β2 integrin, leading to a high affinity open state, which results in strong binding of all ligands [53].…”

Epigenetic clock and methylation study of oocytes from a bovine model of reproductive aging

“…PCOS is a complex disorder characterized by infertility, hirsutism, obesity, various menstrual disturbances, and enlarged ovaries studded with atretic (degenerated) follicles [17][18][19][20].…”