G12-G13 in Cellular Signaling
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G12-G13 in Cellular Signaling

The G12 subfamily of heterotrimeric G-Proteins , comprised of the Alpha-subunits G-Alpha12 and G-Alpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. Activated G-Alpha12 and G-Alpha13 have a molecular weight of 43,000 kDa and they show more than 66% amino acid identity. They stimulate mitogenic signaling pathways leading to the oncogenic transformation of fibroblast cell lines. Recent analyses have indicated that G-Alpha12 and G-Alpha13 regulate cytoplasmic as well as nuclear signaling events through downstream targets such as Ras-,Rac -,Rho -, and CDC42 (Cell Division Cycle-42) dependent pathways, leading to cytoskeletal reorganization and to the activation of MAPK (Mitogen-Activated Protein Kinase), JNK (Jun N-terminal kinase), the Na+-H+(sodium/hydrogen) exchanger, c-Fos, SRE (Serum Response Element) and transcriptional activation of specific primary response genes (Ref.1).

G-Alpha12 and G-Alpha13 have been shown to induce Rho activation and Rho-dependent biological responses, including stress fiber formation and focal adhesion assembly. These G-proteins couple GPCRs (G-protein Coupled Receptors) to the activation of Rho . Recently, two novel RhoGEFs (Rho-specific Guanine nucleotide Exchange Factors), PDZ-RhoGEF and LARG, have been identified to interact with the activated alpha-subunits of G12/13 and are thus believed to mediate GPCR-induced Rho activation (Ref.2). The mechanisms through which G-Alpha12/13 transmits its signals to the different small GTPases are largely unknown. G-Alpha12/13 can stimulate the small GTPases by stimulating specific GEFs (Guanine Nucleotide Exchange Factors), competing with GDIs (Guanine nucleotide Dissociation Inhibitors), or inhibiting specific GAPs (GTPase Activating Proteins). Both G-Alpha12 and G-Alpha13 can physically interact with RGS (Regulator of G-protein Signaling) motif containing RhoGEF . The coupling between G-Alpha12, G-Alpha13 and Rho appear to involve addition mechanisms. Signal coupling between G-Alpha13 and Rho appear to involve RTK (Receptor Tyrosine Kinases) such as EGFR (Epidermal Growth Factor Receptor) and other non-receptor kinases. In contrast, the coupling between G-Alpha12 and Rho appear to be independent of any tyrosine kinases. Similarly a role for BTK (Bruton’s Tyrosine Kinase) family of kinases in G-Alpha12/13 coupling to Rho has been observed. Activated Rho would induce the formation of actin stress fibers and promote the assembly of focal adhesions, resulting in recruitment of p125Fak to focal adhesions and tyrosine phosphorylation of p125Fak, Paxillin, and p130cas (Ref.3).

Lsc (the murine homolog of human p115 RhoGEF) has been identified as a specificGEF for the Rho GTPase. In addition to a DH domain, Lsc contains a RGS (Regulator of G-protein Signaling) domain that downmodulates heterotrimeric G-Proteins by stimulating the intrinsic GTPase activity of the Alpha subunit of the trimer. The Lsc RGS domain is specific for the G-Alpha12 and G-Alpha13 subunits of GPCRs. GPCRs that activate Rho and use G-Alpha12 or G-Alpha13 for signal transduction include receptors for LPA (Lysophosphatidic Acid) and S1-P (Sphingosine 1-Phosphate), Thrombin, TXA2 (Thromboxane-A2) and the orphan receptor G2A. In addition, theG-Alpha13 subunit induces Lsc GEF activity, possibly through the action of binding to the RGS domain. Lsc may therefore have a role in the modulation of signals that emanate from GPCRs by down-regulating G-Alpha12 and G-Alpha13 via the RGS domain while it transmits signals to Rho through the GEF domain (Ref.4). G-Alpha12,G-Alpha13, Lsc and Rho have all been implicated in the activation of SRF (Serum Response Factor), which controls transcription of the cytoskeletal and immediate-early genes required for entry into the cell cycle. The PYK2 (Protein Tyrosine Kinase-2) also known as RAFTK activates a SRE reporter gene downstream of G-Alpha13through a Rho-dependent pathway. PYK2 is itself activated by G-Alpha13, and to a lesser extent by G-Alpha12, and the RGS domain of Lsc blocks activation of PYK2 by G-Alpha12 and G-Alpha13. Rho is upstream of NF-KappaB (Nuclear Factor-KappaB) activation (Ref.5).

G-Alpha12 can also physically interact with a novel Ras-GAP as well as BTK and stimulate their activity. The recent finding that SHC is involved in transmitting the signals from G-Alpha12 to Ras suggests the mechanism through which G-Alpha12 can stimulate Ras. The observation that LPA receptors can activate TIAM1, an exchange factor for Rac through a PKC (Protein Kinase-C) dependent mechanism, suggests an interesting possibility that G-Alpha12, which activates PKC-dependent pathway in some cell types, can stimulate Rac and possibly Rac-mediated JNK activity through PKC and TIAM1.Thus, G-Alpha12/13 coordinates several critical signaling events through its interactions with the Ras- and Rho-family of GTPases. These include the regulation of different kinase modules as well as the activation of several transcription factors such as SRF, TCFs (Ternary Complex Factors), Jun and ATF2 (Activating Transcription Factor-2). Besides, G-Alpha12 is also able to activate SREs through tyrosine kinases of the Tec family. G-Alpha12 is thought to stimulate Phospholipase D, c-Src, and PKC by as-yet unidentified mechanisms. In many cases it appears that different members of the MAPK family, such as ERK5 (Extracellular Signal-Regulated Kinase-5) or JNK, are activated. This activation should lead to regulation of gene expression. G-Alpha13, besides directly interacting with and activating Rho, may also engage the PI3K (Phosphoinositide-3 Kinase) pathway to activate the protein kinase Akt and regulate NF-KappaB , through the activation of PYK2. How G-Alpha13 activates PYK2 is currently not understood (Ref.6).

G12 subfamily proteins, G-Alpha12 and G-Alpha13 also interact with the cytoplasmic domains of several members of the Cadherin family of cell-surface adhesion proteins, causing dissociation of the transcriptional activator from Cadherins. Among proteins previously found to associate with the cadherin cytoplasmic region, Beta-Ctnn (Beta-catenin) is a multifunctional protein that not only serves to link cadherin to the actin cytoskeleton, but also serves as a transcriptional activator. Under resting conditions in the cell, free Beta-Ctnn is targeted for degradation in the cytoplasm by a protein complex that includes the APC (Adenomatous Polyposis Coli) protein. Signaling input from the WNT/Frizzled pathway can block Beta-Ctnn degradation and allow its accumulation in the cytoplasm and nucleus, allowing expression of key genes involved in growth and development. Furthermore, in cells lacking the APC protein required for Beta-Ctnn degradation, expression of mutationally activated G-Alpha12 or G-Alpha13 causes an increase in Beta-Ctnn-mediated transcriptional activation. These findings provide a potential molecular mechanism for the cellular transforming ability of the G-Alpha12 subfamily and reveal a link between heterotrimeric G-proteins and cellular processes controlling growth and differentiation. It has been speculated that the over expression of G-Alpha12 and G-Alpha13 genes may have a causative role in soft tissue sarcomas. However, the signaling mechanisms by which G-Alpha12 and G-Alpha13 regulate cell proliferation is largely unknown. (Ref.7).