RAC1 in cellular processes
Ras-related C3 botulinum toxin substrate 1 (Rac1) is a
member of the RAS superfamily of small GTPases. It plays an essential role in control of
the cell polarity, actin cytoskeleton rearrangements, protein trafficking and directed
motility in a vide variety of mammalian cells , .
GTP-bound Rac1 activates a large number of effector
proteins and promotes various signaling pathways. p21 protein (Rac1/Rac)-activated
kinases 1-3 (PAK1, PAK2,
PAK3) are known as downstream targets of
Rac1. The association between the active GTP form of
Rac1 and the PBD domain of PAK1-3 promotes PAK1-3
autophosphorylation and activation of Mitogen-activated protein kinases 8-10
(JNK (MAPK 8-10)) , , , , . Rac1 can also
activate JNK pathway via PAK- independent mechanism that involves binding and stimulation
of Mitogen-activated protein kinase kinase kinase 11
(MLK3(MAP3K11)) , , .
Rac1 is a critical regulator of NADPH oxidase activity
and assembly in phagocytic cells . NADPH oxidase is a multisubunit
complex that contains Cytochrome b-558, which is a
heterodimer composed of the large Cytochrome b-245, beta polypeptide
(gp91-phox) and small Cytochrome b-245, alpha polypeptide
(p22-phox) subunits. Activation of the oxidase is controlled
by the recruitment to the Cytochrome b-558 of such cytosolic
regulatory proteins as Neutrophil cytosolic factors 1 and 2
(p47-phox and p67-phox) . Rac1 interacts with
p47-phox and p67-phox thus
promoting activation of the NADPH oxidase , .
There are several known pathways through which Rac1
promotes remodeling of the cytoskeleton. One of these pathways is the stimulation by
Rac1 of the actin polymerization by activation of WAS
protein family, members 1 and 2 (WASF1(WAVE1) and
WASF2) , , .
Rac1 binds to NCK-associated protein 1
(NckAP1) and Cytoplasmic FMR1 interacting protein 2
(CYFIP2) and also promotes NCK adaptor protein 1
(NCK1) binding to NckAP1. It
inhibits NckAP1 and CYFIP2
binding to WASF1(WAVE1), and promotes release of the active
complex of WASF1(WAVE1) and the
Chromosome 3 open reading frame 10 (HSPC300). Activated
WASF1(WAVE1) stimulates Actin related protein 2/3 complex
(Arp2/3) that mediates Actin
cytoskeletal polymerization . In addition,
Rac1 binds to BAI1-associated protein 2
(BAIAP2) that in turn associates with
WASF2. This stimulates Arp2/3
and leads to Actin cytoskeletal polymerization , , . In addition,
Rac1 modulates cytoskeleton remodeling by activating
ADP-ribosylation factor interacting protein 2 (POR1) and
Phosphatidylinositol-4-phosphate 5-kinase, type 1 (PIP5KI)
, , .
Rac1 can directly bind to Par-6 partitioning defective 6
homolog (PARD6) that activates Protein kinase C, zeta
(PKC-zeta). This leads to establishment of the cell polarity
and promotes cellular transformation , , .
Activated Rac1 in turn can activate MCF.2 cell line
derived transforming sequence-like (DBS), a common activator
for CDC42 and RhoA .
Dystrophia myotonica-protein kinase (DMPK) and
Phospholipase D1, phosphatidylcholine-specific (PLD1) are
also downstream targets of the Rac1 , .
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