Structure, functional regulation and signaling properties of Rap2B

Abstract

The Ras family small guanosine 5'-triphosphate (GTP)-binding protein Rap2B is is a member of the Ras oncogene family and a novel target of p53 that regulates the p53-mediated pro-survival function of cells. The Rap2B protein shares ~90% homology with Rap2A, and its sequence is 70% identical to other members of the Rap family such as RaplA and RaplB. As a result, Rap2B has been theorized to have similar signaling effectors to the GTPase-binding protein Rap, which mediates various biological functions, including the regulation of sterile 20/mitogen-activated proteins. Since its identification in the early 1990s, Rap2B has elicited a considerable interest. Numerous studies indicate that Rap2B exerts specific biological functions, including binding and stimulating phospholipase C-ε and interferon-γ. In addition, downregulation of Rap2B affects the growth of melanoma cells. The present review summarizes the possible effectors and biological functions of Rap2B. Increasing evidence clearly supports the association between Rap2B function and tumor development. Therefore, it is conceivable that anticancer drugs targeting Rap2B may be generated as novel therapies against cancer.

Keywords: Rap2B; biological function; cancer; effector; structure.

Figure 1.

Domain structure of Rap2B, a Ras family small guanosine 5′-triphosphate-binding protein. Rap2B is composed of an effector domain (amino acids, 32–40), nucleotide binding regions (amino acids, 11–148) and a carboxy-terminal CAAX motif (amino acids, 179–183). The CAAX motif consists of a cysteine followed by two aliphatic residues and one random amino acid. Rap2B terminates with a CVIL motif. C176/C177 are the palmitoylation sites of Rap2B.

Figure 2.

Signaling pathway and biological function of Rap2B, a Ras family small guanosine 5′-triphosphate-binding protein. (A) Rap2B functions as a binary switch. (B) Specific effectors of Rap2B. (C) Rap2B regulates various cellular biological functions by interacting with specific effectors. GAP, GTPase-activating protein; SPA-1, suppressor of phyA-105 1; GTP, guanosine 5′-triphosphate; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factor; Epac, exchange protein directly activated by cyclic adenosine monophosphate; GRP, guanyl-releasing protein; RA, Ras/Rap1A-associating; MAP4K4, mitogen-activated protein kinase kinase kinase kinase 4; MINK, misshapen/NIK-related kinase; NIK, NF-κB–inducing kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TNIK, TRAF2 and NCK-interacting kinase; TRAF2; TNF receptor-associated factor 2; TNF, tumor necrosis factor; NCK, noncatalytic region of tyrosine kinase; RPIP9, Rap2 interacting protein 9; PARG1, PTPL1-associated RhoGAP 1; PLC, phospholipase C.