G-protein signaling - Regulation of RAC1 activity

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Regulation of Rac1 activation

Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the Rho subgroup of a family of small GTP-binding proteins (G-proteins) called monomeric G-proteins. Proteins belonging to the Rho subgroup are involved in cytoskeletal control, regulation of the formation of the stress fibers, focal adhesions, cell growth, membrane trafficking, development, and axon guidance and extension [1].

Rac1 is a target of posttranslational modification via attachment of lipid moieties, such as geranyl, catalyzed by Geranylgeranyltransferase type I (GGTF-I). These posttranslational modifications affect localization and biological activity of Rac1 [2].

Like other G-proteins, Rac1 is found in two interconvertible forms, GDP-bound inactive and GTP-bound active forms.

Conversion from GTP-bound form (active G-protein) to GDP-bound form (inactive G-protein) is a result of intrinsic GTPase activity of Rac1. This activity is slow, and proteins called GTPase activated proteins (GAPs), such as Rho GTPase activating protein 1 (RhoGAP1), Rac GTPase activating protein 1 (RacGAP1), RICS Rho GTPase-activating protein (p200RhoGAP), Rho GTPase activating protein 9 (ARHGAP9), Active BCR-related gene (ABR), Breakpoint cluster region (BCR), Chimerin 2 (B-chimaerin), and RalA binding protein 1 (RalBP1), are known to stimulate it, thereby inactivating G-proteins.

Rho-family proteins are found in the cytosol in the GDP-bound inactive form complexed with GTPase dissociation inhibitors (GDIs), such as Rho GDP dissociation inhibitor alpha and beta (RhoGDI alpha and LyGDI). The GDP-bound form is first released from the GDI via a hitherto unknown mechanism and is converted to the GTP-bound by the Guanine nucleotide exchange factors (GEFs). GEFs activate G-proteins [1].

The several GEFs are known to interact with Rac1. These are Vav 1 and 2 GEFs (VAV-1 and VAV-2), MCF.2 cell line derived transforming sequence (DBL), T-cell lymphoma invasion and metastasis 1 (Tiam1), Epithelial cell transforming sequence 2 oncogene (ECT2), Rho/Rac GEF 2 (ARHGEF2) and others.

The activity of GAPs, GEFs and GDIs is regulated by multiple intracellular processes, but precise pathways involved in these are not apparent.

The most extensively studied GEFs for Rac1 are VAV proteins. VAV-2 is recruited by the CD19 co-receptor of the B cells and participates in the B cell receptor signaling [3]. In the T cell, VAV-1 forms complex with Lymphocyte cytosolic protein 2 (Slp76) linker protein. Complex VAV-1/ Slp76 is involved in the T cell receptor (TCR alpha/beta) and CD28 signaling cascades [4].

Small GTPase pathways can cross-talk. E.g., v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) activates Tiam 1, an exchange factor for Rac1. That leads to Rac1 activation. On the other hand, RalBP1, an effector for v-Ral simian leukemia viral oncogene homolog A and B (RalA and RalB), inactivates Rac1 [5], [6].

References:

  1. Takai Y, Sasaki T, Matozaki T
    Small GTP-binding proteins. Physiological reviews 2001 Jan;81(1):153-208
  2. Kinsella BT, Erdman RA, Maltese WA
    Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA. The Journal of biological chemistry 1991 May 25;266(15):9786-94
  3. Doody GM, Billadeau DD, Clayton E, Hutchings A, Berland R, McAdam S, Leibson PJ, Turner M
    Vav-2 controls NFAT-dependent transcription in B- but not T-lymphocytes. The EMBO journal 2000 Nov 15;19(22):6173-84
  4. Michel F, Acuto O
    CD28 costimulation: a source of Vav-1 for TCR signaling with the help of SLP-76? Science's STKE : signal transduction knowledge environment 2002 Aug 6;2002(144):pe35
  5. Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J, Collard JG, Der CJ
    Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature cell biology 2002 Aug;4(8):621-5
  6. Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH
    Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. The Journal of biological chemistry 1995 Sep 22;270(38):22473-7

  1. Takai Y, Sasaki T, Matozaki T
    Small GTP-binding proteins. Physiological reviews 2001 Jan;81(1):153-208
  2. Kinsella BT, Erdman RA, Maltese WA
    Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA. The Journal of biological chemistry 1991 May 25;266(15):9786-94
  3. Doody GM, Billadeau DD, Clayton E, Hutchings A, Berland R, McAdam S, Leibson PJ, Turner M
    Vav-2 controls NFAT-dependent transcription in B- but not T-lymphocytes. The EMBO journal 2000 Nov 15;19(22):6173-84
  4. Michel F, Acuto O
    CD28 costimulation: a source of Vav-1 for TCR signaling with the help of SLP-76? Science's STKE : signal transduction knowledge environment 2002 Aug 6;2002(144):pe35
  5. Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J, Collard JG, Der CJ
    Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature cell biology 2002 Aug;4(8):621-5
  6. Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, Tavitian A, Gacon G, Camonis JH
    Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. The Journal of biological chemistry 1995 Sep 22;270(38):22473-7

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