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 .
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 .
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
Breakpoint cluster region
(BCR), Chimerin 2
and RalA binding protein 1
(RalBP1), are known to stimulate it, thereby inactivating
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
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)
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 . 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
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 , .
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Small GTP-binding proteins.
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The EMBO journal 2000 Nov 15;19(22):6173-84
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CD28 costimulation: a source of Vav-1 for TCR signaling with the help of SLP-76?
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Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism.
Nature cell biology 2002 Aug;4(8):621-5
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