Search results for PKN2

Showing 13 results out of 13

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Types

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Protein (2 results from a total of 2)

Identifier: R-HSA-5623612
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: PKN2: Q16513
Identifier: R-HSA-5623652
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: PKN2: Q16513

Reaction (7 results from a total of 7)

Identifier: R-HSA-5623622
Species: Homo sapiens
Compartment: plasma membrane, cytosol
Each protein kinase C related kinase - PKN1 (PRK1), PKN2 (PRK2) and PKN3 (PRK3) - possesses three RHO binding motifs known as HR1 (REM) domains - HR1a (REM1), HR1b (REM2) and HR1c (REM3) located at the N-termini of PKN1, PKN2 and PKN3. These domains mediate the binding of each kinase to any of the three RHO family GTPases: RHOA, RHOB and RHOC. HR1 domains of PKN1, PKN2 and PKN3 contain anti-parallel coiled-coil finger (ACC finger) folds (Maesaki et al. 1999, Hutchinson et al. 2011, Hutchinson et al. 2013). RHO GTPase RAC1 also binds and activates PKN1 (Owen et al. 2003, Modha et al. 2008), with the interaction involving HR1a and HR1b RHO-binding motifs of PKN1 and the polybasic region of RAC1, and it also binds to PKN2 (Zong et al. 1999). Binding of RAC1 to PKN3 is likely, based on sequence similarity, but has not been experimentally investigated.
Identifier: R-HSA-5623667
Species: Homo sapiens
Compartment: cytosol, plasma membrane
PDPK1 (PDK1) phosphorylates PKN1, PKN2 and likely PKN3 on a highly conserved threonine residue (T774 of PKN1, T816 of PKN2, T718 of PKN3) in the kinase activation loop. Although phosphorylation of PKN1, PKN2 and PKN3 at other sites may be needed for them to achieve the full catalytic activity, PDPK1-mediated phosphorylation of the activation loop is a necessary step in PKN1, PKN2 and likely PKN3 activation. This reaction happens while the PKN protein is complexed with a RHO GTPase and PIP3-bound PDPK1 (Flynn et al. 2000, Torbett et al. 2003, Dettori et al. 2009).
Identifier: R-HSA-5623632
Species: Homo sapiens
Compartment: plasma membrane
Binding of PKN1, PKN2 or PKN3 to any of the RHO GTP-ases RHOA, RHOB, RHOC or RAC1 enables PKN1, PKN2 and PKN3 to interact with PIP3-activated kinase PDPK1, through the formation of ternary complexes (Flynn et al. 2000, Torbett et al. 2003).
Identifier: R-HSA-9013024
Species: Homo sapiens
Compartment: cytosol, plasma membrane
In its GTP bound active form, plasma membrane associated RHOB (or constitutively active RHOB mutant in the high throughput study by Bagci et al. 2020) binds to the following effectors at the plasma membrane:
CIT (Madaule et al. 1995; Bagci et al. 2020) and its neuron specific isoform CIT 3 (Di Cunto et al. 1998)
DAAM1 (Higashi et al. 2008)
PKN1 (Hutchinson et al. 2013)
PKN2 (Hutchinson et al. 2013; Bagci et al. 2020)
PKN3 (Hutchinson et al. 2013)
ROCK1 (Leung et al. 1996; Bagci et al. 2020)
ROCK2 (Leung et al. 1996; Bagci et al. 2020)
RTKN (Reid et al. 1996)

The following putative RHOB effectors were identified only in the high throughput study by Bagci et al. 2020, where they were shown to bind to the active mutant of RHOB, and are annotated as candidate RHOB effectors:
ACTC1 (Bagci et al. 2020)
ANLN (Bagci et al. 2020)
ARHGAP1 (Bagci et al. 2020)
BCR (Bagci et al. 2020)
CAV1 (Bagci et al. 2020)
CAVIN1 (Bagci et al. 2020)
DEPDC1B (Bagci et al. 2020)
DIAPH3 (Bagci et al. 2020)
ERBIN (Bagci et al. 2020)
FLOT1 (Bagci et al. 2020)
FLOT2 (Bagci et al. 2020)
IQGAP3 (Bagci et al. 2020)
JUP (Bagci et al. 2020)
MCAM (Bagci et al. 2020)
MYO9B (Bagci et al. 2020)
PCDH7 (Bagci et al. 2020)
SLK (Bagci et al. 2020)
SNAP23 (Bagci et al. 2020)
SOWAHC (Bagci et al. 2020)
STK10 (Bagci et al. 2020)
STOM (Bagci et al. 2020)
TFRC (Bagci et al. 2020)
TJP2 (Bagci et al. 2020)
VAMP3 (Bagci et al. 2020)
VANGL1 (Bagci et al. 2020)

Active RHOB does not bind the following effectors:
AAAS (Bagci et al. 2020)
ABCD3 (Bagci et al. 2020)
ACBD5 (Bagci et al. 2020)
ATP6AP1 (Bagci et al. 2020)
BCAP31 (Bagci et al. 2020)
C1QBP (Bagci et al. 2020)
CCDC115 (Bagci et al. 2020)
CCDC187 (Bagci et al. 2020)
DDRGK1 (Bagci et al. 2020)
EMC3 (Bagci et al. 2020)
FAF2 (Bagci et al. 2020)
FMNL2 (Kitzing et al. 2010)
FMNL3 (Bagci et al. 2020)
HMOX2 (Bagci et al. 2020)
IQGAP1 (Casteel et al. 2012)
KIAA0355 (Bagci et al. 2020)
LBR (Bagci et al. 2020)
MACO1 (Bagci et al. 2020)
LMAN1 (Bagci et al. 2020)
PGRMC2 (Bagci et al. 2020)
RHOA (Bagci et al. 2020)
SCFD1 (Bagci et al. 2020)
STBD1 (Bagci et al. 2020)
STX5 (Bagci et al. 2020)
TEX2 (Bagci et al. 2020)
TMEM87A (Bagci et al. 2020)
TMPO (Bagci et al. 2020)
VAPB (Bagci et al. 2020)
YKT6 (Bagci et al. 2020)
Identifier: R-HSA-9013110
Species: Homo sapiens
Compartment: plasma membrane, cytosol
In its GTP bound active form, plasma membrane associated RHOC binds to the following cytosolic and plasma membrane effectors:
CIT (Madaule et al. 1995; Bagci et al. 2020) and its neuron specific isoform CIT 3 (Di Cunto et al. 1998)
DAAM1 (Higashi et al. 2008)
DIAPH1 (Higashi et al. 2008)
FMNL2 (Kitzing et al. 2010, Moriya et al. 2012)
IQGAP1 (Casteel et al. 2012)
PKN1 (Hutchinson et al. 2013)
PKN2 (Hutchinson et al. 2013, Bagci et al. 2020)
PKN3 (Hutchinson et al. 2013)
ROCK1 (Leung et al. 1996, Bagci et al. 2020)
ROCK2 (Leung et al. 1996, Bagci et al. 2020)
RTKN (Reid et al. 1996)

Opposing findings have been reported on the following putative RHOC effectors, or they were identified only in the high throughput study by Bagci et al. 2020, where they were shown to bind to the active mutant of RHOC; they are therefore annotated as candidate RHOC effectors:
ABCD3 (Bagci et al. 2020)
ACBD5 (Bagci et al. 2020)
ANLN (Bagci et al. 2020)
ARHGAP1 (Bagci et al. 2020)
BCR (Bagci et al. 2020)
C1QBP (Bagci et al. 2020)
CAV1 (Bagci et al. 2020)
CAVIN1 (Bagci et al. 2020)
CCDC187 (Bagci et al. 2020)
DEPDC1B (Bagci et al. 2020)
DIAPH3 (Bagci et al. 2020)
ERBIN (Bagci et al. 2020)
FLOT1 (Bagci et al. 2020)
FLOT2 (Bagci et al. 2020)
FMNL3 (Vega et al. 2011: binds to activated RHOC; Bagci et al. 2020: does not bind to active RHOC)
IQGAP3 (Bagci et al. 2020)
JUP (Bagci et al. 2020)
MCAM (Bagci et al. 2020)
MYO9B (Bagci et al. 2020)
RHOA (Bagci et al. 2020)
SLK (Bagci et al. 2020)
STBD1 (Bagci et al. 2020)
STK10 (Bagci et al. 2020)
STOM (Bagci et al. 2020)
TJP2 (Bagci et al. 2020)
TFRC (Bagci et al. 2020)
TMPO (Bagci et al. 2020)
VAMP3 (Bagci et al. 2020)
VANGL1 (Bagci et al. 2020)

Active RHOC does not bind to
AAAS (Bagci et al. 2020)
ACTC1 (Bagci et al. 2020)
ATP6AP1 (Bagci et al. 2020)
BCAP31 (Bagci et al. 2020)
CCDC115 (Bagci et al. 2020)
DDRGK1 (Bagci et al. 2020)
EMC3 (Bagci et al. 2020)
FAF2 (Bagci et al. 2020)
HMOX2 (Bagci et al. 2020)
KIAA0355 (Bagci et al. 2020)
PCDH7 (Bagci et al. 2020)
SCFD1 (Bagci et al. 2020)
SNAP23 (Bagci et al. 2020)
SOWAHC (Bagci et al. 2020)
TEX2 (Bagci et al. 2020)
TMEM87A (Bagci et al. 2020)
FMNL3 (Bagci et al. 2020)
YKT6 (Bagci et al. 2020)
Identifier: R-HSA-9013009
Species: Homo sapiens
Compartment: plasma membrane
In its GTP bound active form, plasma membrane associated RHOA (or constitutively active RHOA mutant in the high throughput study by Bagci et al. 2020) binds to the following effectors:
ANLN (Piekny and Glotzer 2008; Budnar et al. 2019; Bagci et al. 2020)
CIT (Madaule et al. 1995; Bagci et al. 2020) and its neuron specific splicing isoform CIT 3 (Di Cunto et al. 1998)
DAAM1 (Aspenstrom et al. 2006; Higashi et al. 2008)
DIAPH1 (Otomo et al. 2005; Higashi et al. 2008; Lammers et al. 2008; Gao et al. 2009; Li and Sewer 2010; Bagci et al. 2020)
DIAPH3 (Alberts et al. 1998; Watanabe et al. 2010; Staus et al. 2011; Chen et al. 2017; Bagci et al. 2020)
IQGAP1 (Casteel et al. 2012)
PKN1 (Maesaki et al. 1999; Hutchinson et al. 2011; Hutchinson et al. 2013)
PKN2 (Hutchinson et al. 2013; Bagci et al. 2020)
PKN3 (Hutchinson et al. 2013)
PLD1 (Hammond et al. 1997; Yamazaki et al. 1999)
RHPN1 (Watanabe et al. 1996; Peck et al. 2002)
RHPN2 (Peck et al. 2002)
ROCK1 (Ishizaki et al. 1996; Leung et al. 1996; Bagci et al. 2020)
ROCK2 (Leung et al. 1996; Bagci et al. 2020)
RTKN (Reid et al. 1996; Fu et al. 2000)
SLK (Bagci et al. 2020: interaction and activation of SLK downstream of RHOA confirmed in detail)
STK10 (Bagci et al. 2020: interaction corroborated by additional experimental methods)

The following putative RHOA effectors are annotated as candidates either because of opposing findings reported by different studies or because their binding to RHOA was only shown in the context of constitutively active RHOA mutant in the high throughput screen by Bagci et al. 2020:
AAAS (Bagci et al. 2020)
ABCD3 (Bagci et al. 2020)
ACBD5 (Bagci et al. 2020)
ACTC1 (Bagci et al. 2020)
ARHGAP1 (Bagci et al. 2020)
BCR (Bagci et al. 2020)
C1QBP (Bagci et al. 2020)
CAV1 (Bagci et al. 2020)
CAVIN1 (Bagci et al. 2020)
DEPDC1B (Bagci et al. 2020)
ERBIN (Bagci et al. 2020)
FAF2 (Bagci et al. 2020)
FLOT1 (Bagci et al. 2020)
FLOT2 (Bagci et al. 2020)
FMNL3 (Bagci et al. 2020: binding to RHOA; Vega et al. 2011: no binding to RHOA)
HMOX2 (Bagci et al. 2020)
IQGAP3 (Bagci et al. 2020)
JUP (Bagci et al. 2020)
MCAM (Bagci et al. 2020)
MYO9B (Bagci et al. 2020)
PCDH7 (Bagci et al. 2020)
SCFD1 (Bagci et al. 2020)
SNAP23 (Bagci et al. 2020)
SOWAHC (Bagci et al. 2020)
STBD1 (Bagci et al. 2020)
STOM (Bagci et al. 2020)
TFRC (Bagci et al. 2020)
TJP2 (Bagci et al. 2020)
TMPO (Bagci et al. 2020)
VAMP3 (Bagci et al. 2020)
VANGL1 (Bagci et al. 2020)

RHOA does not bind the following effectors:
CCDC187 (Bagci et al. 2020)
CDC42BPA (Leung et al. 1998)
CDC42BPB (Leung et al. 1998)
CDC42EP1 (Joberty et al. 1999)
CDC42EP2 (Joberty et al. 1999)
CDC42EP3 (Joberty et al. 1999)
CDC42EP4 (Joberty et al. 1999)
CDC42EP5 (Joberty et al. 1999)
FMNL2 (Kitzing et al. 2010)
IQGAP2 (Brill et al. 1996)
KIAA0355 (Bagci et al. 2020)
PLD2 (Kodaki and Yamashita 1997)
WAS (WASP) (Aspenstrom et al. 1996)
Identifier: R-HSA-9013145
Species: Homo sapiens
Compartment: plasma membrane, cytosol
In its GTP bound active form, plasma membrane associated RAC1 binds to the following cytosolic and plasma membrane effectors:
BAIAP2 (Lewis Saravalli et al. 2013, Bagci et al. 2020)
CAV1 (Nethe et al. 2010, Bagci et al. 2020)
CDC42BPA (Schwarz et al. 2012)
CIT (Madaule et al. 1995)
CIT 3 (Di Cunto et al. 1998)
CYFIP1 (Schneck et al. 2003, Bagci et al. 2020)
FMNL1 (Yayoshi Yamamoto et al. 2000)
IQGAP1 (Kuroda et al. 1996, Pelikan Conchaudron et al. 2011)
IQGAP2 (Brill et al. 1996, Ozdemir et al. 2018)
IQGAP3 (Wang et al. 2007)
KIAA0355 (Bagci et al. 2020: interaction studied in detail)
NISCH (Reddig et al. 2005)
NOX1 complex (Cheng et al. 2006, Miyano et al. 2006, Kao et al. 2008)
NOX2 complex (Price et al. 2002)
NOX3 complex (Ueyama et al. 2006, Miyano and Sumimoto 2007, Kao et al. 2008)
PAK1 (Parrini et al. 2002)
PAK2 (Manser et al. 1994, Manser et al. 1995, Bagci et al. 2020)
PAK3 (Manser et al. 1995)
PAK4 (Abo et al. 1998, Bagci et al. 2020)
PAK5 (Dan et al. 2002)
PAK6 (Lee et al. 2002)
PARD6A (Qiu et al. 2000)
PI3K alpha (Bokoch et at al. 1996, Murga et al. 2002)
PKN1 (Owen et al. 2003, Modha et al. 2008)
PKN2 (Zong et al. 1999)
PLD1 (Hammond et al. 1997)
PLD2 (Hiroyama and Exton 2005)
WAVE complex (Miki et al. 1998, Suetsugu et al. 2006, Bagci et al. 2020)

The following RAC1 effectors are annotated as candidate effectors either because of opposing finding reported in different studies or because they have only been reported in the high throughput screen by Bagci et al. 2020:
ABI1 (Bagci et al. 2020)
ABL2 (Bagci et al. 2020)
AMIGO2 (Bagci et al. 2020)
ARAP2 (Bagci et al. 2020)
BAIAP2L1 (Bagci et al. 2020)
BRK1 (Bagci et al. 2020)
CDC42 (Bagci et al. 2020)
CDC42EP1 (Bagci et al. 2020: binding to activated RAC1; Joberty et al. 1999: no binding to activated RAC1)
CDC42EP4 (Bagci et al. 2020: binding to activated RAC1; Joberty et al. 1999: no binding to activated RAC1)
DEPDC1B (Bagci et al. 2020)
DIAPH3 (Bagci et al. 2020)
EPHA2 (Bagci et al. 2020)
ERBIN (Bagci et al. 2020)
FERMT2 (Bagci et al. 2020)
GIT1 (Bagci et al. 2020)
GIT2 (Bagci et al. 2020)
ITGB1 (Bagci et al. 2020)
JAG1 (Bagci et al. 2020)
LAMTOR1 (Bagci et al. 2020)
MCAM (Bagci et al. 2020)
MPP7 (Bagci et al. 2020)
NCKAP1 (Bagci et al. 2020)
NHS (Bagci et al. 2020)
PLEKHG3 (Bagci et al. 2020)
PLEKHG4 (Bagci et al. 2020)
RAB7A (Bagci et al. 2020)
SLC1A5 (Bagci et al. 2020)
SNAP23 (Bagci et al. 2020)
SWAP70 (Bagci et al. 2020)
TAOK3 (Bagci et al. 2020)
TFRC (Bagci et al. 2020)
TMPO (Bagci et al. 2020)
VAMP3 (Bagci et al. 2020)
VANGL1 (Bagci et al. 2020)
WIP WASP complex (WAS, also known as WASP, a component of the WIP WASP complex, was reported to interact with active RAC1 by Aspenstrom et al. 1996 and Vastrik et al. 1999, but no interaction has been reported between RAC1 and WIP components of the complex, WIPF1, WIPF2 or WIPF3)

Active RAC1 does not bind the following RHO GTPase effectors:
ANKLE2 (Bagci et al. 2020)
ARFGAP3 (Bagci et al. 2020)
ARMCX3 (Bagci et al. 2020)
CDC42EP2 (Joberty et al. 1999)
CDC42EP3 (Joberty et al. 1999)
CDC42EP5 (Joberty et al. 1999)
DSG2 (Bagci et al. 2020)
DIAPH1 (Higashi et al. 2008)
DOCK1 (Bagci et al. 2020)
DOCK5 (Bagci et al. 2020)
ELMO2 (Bagci et al. 2020)
FMNL2 (Block et al. 2012)
HSPE1 (Bagci et al. 2020)
IL32 (Bagci et al. 2020)
LETM1 (Bagci et al. 2020)
LMAN1 (Bagci et al. 2020)
NDUFA5 (Bagci et al. 2020)
NDUFS3 (Bagci et al. 2020)
PGRMC2 (Bagci et al. 2020)
RAPGEF1 (Bagci et al. 2020)
ROCK1 (Leung et al. 1996)
ROCK2 (Leung et al. 1996)
RTKN (Reid et al. 1996)
SHMT2 (Bagci et al. 2020)
SLK (Yamada et al. 2000)
SLITRK3 (Bagci et al. 2020)
SLITRK5 (Bagci et al. 2020)
STBD1 (Bagci et al. 2020)
STX5 (Bagci et al. 2020)
VAPB (Bagci et al. 2020)

Set (1 results from a total of 1)

Identifier: R-HSA-5623659
Species: Homo sapiens
Compartment: cytosol

Pathway (3 results from a total of 3)

Identifier: R-HSA-5625740
Species: Homo sapiens
Protein kinases N (PKN), also known as protein kinase C-related kinases (PKR) feature a C-terminal serine/threonine kinase domain and three RHO-binding motifs at the N-terminus. RHO GTPases RHOA, RHOB, RHOC and RAC1 bind PKN1, PKN2 and PKN3 (Maesaki et al. 1999, Zhong et al. 1999, Owen et al. 2003, Modha et al. 2008, Hutchinson et al. 2011, Hutchinson et al. 2013), bringing them in proximity to the PIP3-activated co-activator PDPK1 (PDK1) (Flynn et al. 2000, Torbett et al. 2003). PDPK1 phosphorylates PKNs on a highly conserved threonine residue in the kinase activation loop, which is a prerequisite for PKN activation. Phosphorylation of other residues might also be involved in activation (Flynn et al. 2000, Torbett et al. 2003, Dettori et al. 2009). PKNs are activated by fatty acids like arachidonic acid and phospholipids in vitro, but the in vivo significance of this activation remains unclear (Palmer et al. 1995, Yoshinaga et al. 1999).

PKNs play important roles in diverse functions, including regulation of cell cycle, receptor trafficking, vesicle transport and apoptosis. PKN is also involved in the ligand-dependent transcriptional activation by the androgen receptor. More than 20 proteins and several peptides have been shown to be phosphorylated by PKN1 and PKN2, including CPI-17 (Hamaguchi et al. 2000), alpha-actinin (Mukai et al. 1997), adducin (Collazos et al. 2011), CDC25C (Misaki et al. 2001), vimentin (Matsuzawa et al. 1997), TRAF1 (Kato et al. 2008), CLIP170 (Collazos et al. 2011) and EGFR (Collazos et al. 2011). There are no known substrates for PKN3 (Collazos et al. 2011).

Identifier: R-HSA-195258
Species: Homo sapiens
RHO GTPases regulate cell behaviour by activating a number of downstream effectors that regulate cytoskeletal organization, intracellular trafficking and transcription (reviewed by Sahai and Marshall 2002).

One of the best studied RHO GTPase effectors are protein kinases ROCK1 and ROCK2, which are activated by binding RHOA, RHOB or RHOC. ROCK1 and ROCK2 phosphorylate many proteins involved in the stabilization of actin filaments and generation of actin-myosin contractile force, such as LIM kinases and myosin regulatory light chains (MRLC) (Amano et al. 1996, Ishizaki et al. 1996, Leung et al. 1996, Ohashi et al. 2000, Sumi et al. 2001, Riento and Ridley 2003, Watanabe et al. 2007).

PAK1, PAK2 and PAK3, members of the p21-activated kinase family, are activated by binding to RHO GTPases RAC1 and CDC42 and subsequent autophosphorylation and are involved in cytoskeleton regulation (Manser et al. 1994, Manser et al. 1995, Zhang et al. 1998, Edwards et al. 1999, Lei et al. 2000, Parrini et al. 2002; reviewed by Daniels and Bokoch 1999, Szczepanowska 2009).

RHOA, RHOB, RHOC and RAC1 activate protein kinase C related kinases (PKNs) PKN1, PKN2 and PKN3 (Maesaki et al. 1999, Zong et al. 1999, Owen et al. 2003, Modha et al. 2008, Hutchinson et al. 2011, Hutchinson et al. 2013), bringing them in proximity to the PIP3-activated PDPK1 (PDK1) and thus enabling PDPK1-mediated phosphorylation of PKN1, PKN2 and PKN3 (Flynn et al. 2000, Torbett et al. 2003). PKNs play important roles in cytoskeleton organization (Hamaguchi et al. 2000), regulation of cell cycle (Misaki et al. 2001), receptor trafficking (Metzger et al. 2003) and apoptosis (Takahashi et al. 1998). PKN1 is also involved in the ligand-dependent transcriptional activation by the androgen receptor (Metzger et al. 2003, Metzger et al. 2005, Metzger et al. 2008).

Citron kinase (CIT) binds RHO GTPases RHOA, RHOB, RHOC and RAC1 (Madaule et al. 1995), but the mechanism of CIT activation by GTP-bound RHO GTPases has not been elucidated. CIT and RHOA are implicated to act together in Golgi apparatus organization through regulation of the actin cytoskeleton (Camera et al. 2003). CIT is also involved in the regulation of cytokinesis through its interaction with KIF14 (Gruneberg et al. 2006, Bassi et al. 2013, Watanabe et al. 2013).

RHOA, RHOG, RAC1 and CDC42 bind kinectin (KTN1), a kinesin anchor protein involved in kinesin-mediated vesicle motility (Vignal et al. 2001, Hotta et al. 1996). The effect of RHOG activity on cellular morphology, exhibited in the formation of microtubule-dependent cellular protrusions, depends both on RHOG interaction with KTN1, as well as on the kinesin activity (Vignal et al. 2001). RHOG and KTN1 also cooperate in microtubule-dependent lysosomal transport (Vignal et al. 2001).

IQGAP proteins IQGAP1, IQGAP2 and IQGAP3, bind RAC1 and CDC42 and stabilize them in their GTP-bound state (Kuroda et al. 1996, Swart-Mataraza et al. 2002, Wang et al. 2007). IQGAPs bind F-actin filaments and modulate cell shape and motility through regulation of G-actin/F-actin equilibrium (Brill et al. 1996, Fukata et al. 1997, Bashour et al. 1997, Wang et al. 2007, Pelikan-Conchaudron et al. 2011). Binding of IQGAPs to F-actin is inhibited by calmodulin (Bashour et al. 1997, Pelikan-Conchaudron et al. 2011). IQGAP1 is involved in the regulation of adherens junctions through its interaction with E-cadherin (CDH1) and catenins (CTTNB1 and CTTNA1) (Kuroda et al. 1998, Hage et al. 2009). IQGAP1 contributes to cell polarity and lamellipodia formation through its interaction with microtubules (Fukata et al. 2002, Suzuki and Takahashi 2008).

RHOQ (TC10) regulates the trafficking of CFTR (cystic fibrosis transmembrane conductance regulator) by binding to the Golgi-associated protein GOPC (also known as PIST, FIG and CAL). In the absence of RHOQ, GOPC bound to CFTR directs CFTR for lysosomal degradation, while GTP-bound RHOQ directs GOPC:CFTR complex to the plasma membrane, thereby rescuing CFTR (Neudauer et al. 2001, Cheng et al. 2005).

RAC1 and CDC42 activate WASP and WAVE proteins, members of the Wiskott-Aldrich Syndrome protein family. WASPs and WAVEs simultaneously interact with G-actin and the actin-related ARP2/3 complex, acting as nucleation promoting factors in actin polymerization (reviewed by Lane et al. 2014).

RHOA, RHOB, RHOC, RAC1 and CDC42 activate a subset of formin family members. Once activated, formins bind G-actin and the actin-bound profilins and accelerate actin polymerization, while some formins also interact with microtubules. Formin-mediated cytoskeletal reorganization plays important roles in cell motility, organelle trafficking and mitosis (reviewed by Kuhn and Geyer 2014).

Rhotekin (RTKN) and rhophilins (RHPN1 and RHPN2) are effectors of RHOA, RHOB and RHOC and have not been studied in detail. They regulate the organization of the actin cytoskeleton and are implicated in the establishment of cell polarity, cell motility and possibly endosome trafficking (Sudo et al. 2006, Watanabe et al. 1996, Fujita et al. 2000, Peck et al. 2002, Mircescu et al. 2002). Similar to formins (Miralles et al. 2003), cytoskeletal changes triggered by RTKN activation may lead to stimulation of SRF-mediated transcription (Reynaud et al. 2000).

RHO GTPases RAC1 and RAC2 are needed for activation of NADPH oxidase complexes 1, 2 and 3 (NOX1, NOX2 and NOX3), membrane associated enzymatic complexes that use NADPH as an electron donor to reduce oxygen and produce superoxide (O2-). Superoxide serves as a secondary messenger and also directly contributes to the microbicidal activity of neutrophils (Knaus et al. 1991, Roberts et al. 1999, Kim and Dinauer 2001, Jyoti et al. 2014, Cheng et al. 2006, Miyano et al. 2006, Ueyama et al. 2006).

Identifier: R-HSA-194315
Species: Homo sapiens
The Rho family of small guanine nucleotide binding proteins is one of seven phylogenetic branches of the Ras superfamily (Bernards 2005), which, besides Rho, Miro and RHOBTB3 also includes Ran, Arf, Rab and Ras families (Boureux et al. 2007). Miro GTPases and RHOBTB3 ATPase are sometimes described as Rho family members, but they are phylogenetically distinct (Boureux et al. 2007). Phylogenetically, RHO GTPases can be grouped into four clusters. The first cluster consists of three subfamilies: Rho, RhoD/RhoF and Rnd. The second cluster consists of three subfamilies: Rac, Cdc42 and RhoU/RhoV. The third cluster consists of the RhoH subfamily. The fourth cluster consists of the RhoBTB subfamily. Based on their activation type, RHO GTPases can be divided into classical (typical) and atypical (reviewed by Haga and Ridley 2016, and Kalpachidou et al. 2019). Classical RHO GTPases cycle between active GTP-bound states and inactive GDP-bound states through steps that are tightly controlled by members of three classes of proteins: (1) guanine nucleotide dissociation inhibitors or GDIs, which maintain Rho proteins in an inactive state in the cytoplasm, (2) guanine nucleotide exchange factors or GEFs, which destabilize the interaction between Rho proteins and their bound nucleotide, the net result of which is the exchange of bound GDP for the more abundant GTP, and (3) GTPase activating proteins or GAPs, which stimulate the low intrinsic GTP hydrolysis activity of Rho family members, thus promoting their inactivation. GDIs, GEFs, and GAPs are themselves subject to tight regulation, and the overall level of Rho activity reflects the balance of their activities. Many of the Rho-specific GEFs, GAPs, and GDIs act on multiple Rho GTPases, so that regulation of these control proteins can have complex effects on the functions of multiple Rho GTPases (reviewed by Van Aelst and D'Souza-Schorey 1997, Schmidt and Hall 2002, Jaffe and Hall 2005, Bernards 2005, and Hodge and Ridley 2016). Classical RHO GTPases include four subfamilies: Rho (includes RHOA, RHOB and RHOC), Rac (includes RAC1, RAC2, RAC3 and RHOG), Cdc42 (includes CDC42, RHOJ and RHOQ) and RhoD/RhoF (includes RHOD and RHOF) (reviewed in Haga and Ridley 2016). Atypical RHO GTPases do not possess GTPase activity. They therefore constitutively exist in the active GTP-bound state. Atypical RHO GTPases include three subfamilies: Rnd (includes RND1, RND2 and RND3), RhoBTB (includes RHOBTB1 and RHOBTB2), RhoH (RHOH is the only member) and RhoU/RhoV (includes RHOU and RHOV). Members of the Rho family have been identified in all eukaryotes. Among Rho GTPases, RHOA, RAC1 and CDC42 have been most extensively studied.

RHO GTPases regulate cell behavior by activating a number of downstream effectors that regulate cytoskeletal organization, intracellular trafficking and transcription (reviewed by Sahai and Marshall 2002). They are best known for their ability to induce dynamic rearrangements of the plasma membrane-associated actin cytoskeleton (Aspenstrom et al. 2004; Murphy et al. 1999; Govek et al. 2005). Beyond this function, Rho GTPases also regulate actomyosin contractility and microtubule dynamics. Rho mediated effects on transcription and membrane trafficking are believed to be secondary to these functions. At the more macroscopic level, Rho GTPases have been implicated in many important cell biological processes, including cell growth control, cytokinesis, cell motility, cell-cell and cell-extracellular matrix adhesion, cell transformation and invasion, and development (Govek et al., 2005). One of the best studied RHO GTPase effectors are protein kinases ROCK1 and ROCK2, which phosphorylate many proteins involved in the stabilization of actin filaments and generation of actin-myosin contractile force, such as LIM kinases and myosin regulatory light chains (MRLC) (reviewed in Riento and Ridley 2003). The p21-activated kinase family, which includes PAK1, PAK2 and PAK3, is another well characterized family of RHO GTPase effectors involved in cytoskeleton regulation (reviewed in Daniels and Bokoch 1999, Szczepanowska 2009). Protein kinase C related kinases (PKNs), PKN1, PKN2 and PKN3 play important roles in cytoskeleton organization (Hamaguchi et al. 2000), regulation of cell cycle (Misaki et al. 2001), receptor trafficking (Metzger et al. 2003), apoptosis (Takahashi et al. 1998), and transcription (Metzger et al. 2003, Metzger et al. 2005, Metzger et al. 2008). Citron kinase (CIT) is involved in Golgi apparatus organization through regulation of the actin cytoskeleton (Camera et al. 2003) and in the regulation of cytokinesis (Gruneberg et al. 2006, Bassi et al. 2013, Watanabe et al. 2013). Kinectin (KTN1), a kinesin anchor protein, is a RHO GTPase effector involved in kinesin-mediated vesicle motility (Vignal et al. 2001, Hotta et al. 1996), including microtubule-dependent lysosomal transport (Vignal et al. 2001). IQGAP proteins, IQGAP1, IQGAP2 and IQGAP3, are RHO GTPase effectors that modulate cell shape and motility through regulation of G-actin/F-actin equilibrium (Brill et al. 1996, Fukata et al. 1997, Bashour et al. 1997, Wang et al. 2007, Pelikan-Conchaudron et al. 2011), regulate adherens junctions (Kuroda et al. 1998, Hage et al. 2009), and contribute to cell polarity and lamellipodia formation (Fukata et al. 2002, Suzuki and Takahashi 2008). WASP and WAVE proteins (reviewed by Lane et al. 2014), as well as formins (reviewed by Kuhn and Geyer 2014), are RHO GTPase effectors that regulate actin polymerization and play important roles in cell motility, organelle trafficking and mitosis. Rhotekin (RTKN) and rhophilins (RHPN1 and RHPN2) are RHO GTPase effectors that regulate the organization of the actin cytoskeleton and are implicated in the establishment of cell polarity, cell motility and possibly endosome trafficking (Sudo et al. 2006, Watanabe et al. 1996, Fujita et al. 2000, Peck et al. 2002, Mircescu et al. 2002). Cytoskeletal changes triggered by the activation of formins (Miralles et al. 2003) and RTKN (Reynaud et al. 2000) may lead to stimulation of SRF-mediated transcription. NADPH oxidase complexes 1, 2 and 3 (NOX1, NOX2 and NOX3), membrane associated enzymatic complexes that use NADPH as an electron donor to reduce oxygen and produce superoxide (O2-), are also regulated by RHO GTPases (Knaus et al. 1991, Roberts et al. 1999, Kim and Dinauer 2001, Jyoti et al. 2014, Cheng et al. 2006, Miyano et al. 2006, Ueyama et al. 2006). Every RHO GTPase activates multiple downstream effectors and most effectors are regulated by multiple RHO GTPases, resulting in an elaborate cross-talk.
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