Rap1 Pathway
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Rap1 Pathway

Rap1 (Krev-1/smg p21), a small-molecular weight GTP-binding protein that belongs to the Ras-like superfamily of GTPases, is involved in signal transduction cascades. It is highly homologous to Ras but it is down regulated by its own set of GAPs (GTPase-Activating Proteins). Rap1 is implicated in the regulation of a variety of cellular processes including the control of platelet activation, T-cell anergy, B-Cell activation, and neuronal differentiation. Very recently, Rap was shown to be involved in the control of cell adhesion, in particular the regulation of integrin activation by inside-out signaling. In humans, four isoforms of Rap, Rap1A, Rap1B, Rap2A, and Rap2B, exist. Rap1A and Rap1B share more than 90% sequence identity. Rap1A/B is the closest relative of the Ras protein with more than 50% sequence identity. By contrast, Rap1 and Rap2 proteins are only 60% identical to each other, showing noticeable variations at their C-terminus. Just as Ras, it cycles between a GDP-bound inactive and a GTP-bound active form, and this switching is regulated by specific GEFs (Guanine Nucleotide Exchange Factors) and GAPs. A large variety of extracellular stimuli, including growth factors, cytokines, and cell adhesion molecules, regulate Rap1. The latest additions to this list include adhesive surfaces, Ephrin and Ephrin kinases, adenosine diphosphate, the NMDA neurotransmitter, hyperosmotic and cold stresses, IL-1 (Interleukin-1), SDF1 (Stromal Cell-Derived Factor-1), CD98 crosslinking, CD31 crosslinking, LPS (Lipopolysaccharide) and Antigen-Loaded Antigen-Presenting Cells (Ref.1).

Rap1 circulates between GTP-bound active and GDP-bound inactive states. The activation is induced by GEFs; these include C3G, smgGDS, CalDAG-GEFI, PDZ-GEF/RA-GEF/CNrasGEF/nRapGEP1 and EPAC (Exchange Protein Activated by cAMP), which are activated by tyrosine kinases, Ca2+/calmodulin and DAG (Diacylglycerol), and cAMP, respectively. Thus, many signals converge at Rap1 via different GEFs. There are four GAPs of Rap1: Rap1GAP, SPA-1, GAP1IP48P, and Tuberin. Little is known about the regulation of these GAPs, except for that of an isoform of Rap1GAP, Rap1GAPII, which has recently been shown to bind to and transduce signal from the Alpha subunit of heterotrimeric GI protein (Ref.2).

Rap1 structure is highly homologous to that of Ras. Rap1 was originally identified by its ability to reverse cellular transformation induced by oncogenic Ras. Rap1 is more than 50% identical to Ras and is thought to block the mitogenic activity of the cell by trapping the Ras effector c-Raf into an inactive complex, silencing MAPK (Mitogen-Activated Protein Kinases) activity. However, many recent findings suggest that Rap1 could act as an activator of the MAPK pathway in other cellular contexts. For example, Rap1 was found to interact with and activate BRaf, resulting in sustained MAPK activation. It is not clear whether Rap1 acts in a signaling pathway parallel to or independent from Ras, or whether the ability of Rap1 to antagonize or complement Ras-induced transformation is an indirect effect of Rap1 function (Ref.3).

In addition to its ability to modulate Ras-induced transformation, other roles for Rap1 have been proposed. For instance, Rap1 associates with cytochrome B558 in a phosphorylation-dependent manner, and Rap1 may modulate the oxidative burst in phagocytic cells. Also, a Rap1 homologue exists in yeast (RSR/BUD1) that is required for bud site localization, indicating a potential role for Rap1 in regulating actin cytoskeleton rearrangements. Furthermore, it has been shown that Rap1 is a substrate for PKA (Protein Kinase-A). Rap1 can enhance the activity of PKC (Protein Kinase-C), indicating that Rap1 may play a role in an intracellular signaling pathway leading to PKC activation. Finally, it has been demonstrated that Rap1A and Rap1B associate with endocytic and phagocytic compartments in mammalian cells, implicating Rap1 in the regulation of endocytic processes, whereas Rap2A associates with the Golgi. Thus, the proposed functions of this protein, although quite diverse, suggest that Rap1 may regulate endocytosis and/or phagocytosis.

Rap1 is also activated by cAMP. cAMP-dependent activation of Rap1 has been ascribed to the phosphorylation of Rap1A by PKA, which increases its binding affinity for smgGDS, a GEF with broad substrate specificity. The activation of Rap1A induced by cAMP-GEFI and cAMP-GEFII is independent of the PKA pathway. Rap1, like cAMP, activates the ERK cascade via a pathway that is independent of Ras but requires MEK. The actions of Rap1 are dictated by the expression of BRaf. In the absence of BRaf, Rap1 antagonizes Ras-dependent signaling. In the presence of BRaf, Rap1 can positively couple to ERK (Extracellular Signal Regulated Kinases) (Ref.4).

TCR (T-Cell Receptor) engagement triggers the rapid activation of protein tyrosine kinases and the consequent phosphorylation of downstream substrate proteins in the T-cell cytoplasm. These events initiate at least two possible pathways that lead to Rap1A activation. The first pathway involves the tyrosine phosphorylation of Cbl, and the subsequent binding of the CrkL-C3G complex to Cbl. C3G is a GEF that mediates loading of GTP onto Rap1A and consequent Rap1A activation. The second pathway begins with TCR-dependent Ras activation, which may occur through at least two Ras-specific GEFs: the GRB2-SOS (Growth Factor Receptor Bound Protein-2- Son of Sevenless) complex or CD (Calcium-Diacylglycerol)-GEFII (also called RasGRP). In turn, GTP-bound Ras binds to and activates PLC-Epsilon. In addition to an RBD, PLC-Epsilon shows GEF activity for Rap1A. PLC-Epsilon translocates to the perinuclear region, where it binds to and loads GTP onto Rap1A. ADAP (Adhesion and Degranulation Adaptor Protein) is a strong candidate for signal relay between the TCR and Rap1A; it may function in either or both pathways of Rap1A activation. BCR (B-Cell antigen Receptor) engagement also activates Rap1 and that this is dependent on production of DAG by PLC-Gamma (Phospholipase-C-Gamma). The Rap1GTPases may be negative regulators of Ras-mediated signaling. Rap1 functions as a negative regulator of TCR-mediated IL-2 gene transcription and may be responsible for the specific defect in IL-2 production in T-cell anergy. Rap1 controls adhesion-related functions such as phagocytosis, cell-cell contacts and functional activation of integrins through inside-out signaling. Whereas the precise mechanism by which its downstream effectors exert these diverse functions is unknown, Rap1 seems to fulfil the evolutionarily conserved function of patterning the eukaryotic cell, thus enabling it to respond to its environment, in particular through cytoskeletal remodelling (Ref.5).