ID PAK3_RAT Reviewed; 544 AA.
AC Q62829;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 27-MAR-2024, entry version 187.
DE RecName: Full=Serine/threonine-protein kinase PAK 3;
DE EC=2.7.11.1;
DE AltName: Full=Beta-PAK;
DE AltName: Full=p21-activated kinase 3;
DE Short=PAK-3;
DE AltName: Full=p65-PAK;
GN Name=Pak3;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 37-56.
RC TISSUE=Brain;
RX PubMed=7559638; DOI=10.1074/jbc.270.42.25070;
RA Manser E., Chong C., Zhao Z.-S., Leung T., Michael G., Hall C., Lim L.;
RT "Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase
RT (PAK) family.";
RL J. Biol. Chem. 270:25070-25078(1995).
RN [2]
RP FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH APP, AND MUTAGENESIS OF
RP LYS-297 AND THR-421.
RX PubMed=12890786; DOI=10.1523/jneurosci.23-17-06914.2003;
RA McPhie D.L., Coopersmith R., Hines-Peralta A., Chen Y., Ivins K.J.,
RA Manly S.P., Kozlowski M.R., Neve K.A., Neve R.L.;
RT "DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease
RT mutants of the amyloid precursor protein are mediated by the p21 activated
RT kinase PAK3.";
RL J. Neurosci. 23:6914-6927(2003).
RN [3]
RP PHOSPHORYLATION AT SER-50; SER-139 AND THR-421.
RX PubMed=11278486; DOI=10.1074/jbc.m009316200;
RA Chong C., Tan L., Lim L., Manser E.;
RT "The mechanism of PAK activation. Autophosphorylation events in both
RT regulatory and kinase domains control activity.";
RL J. Biol. Chem. 276:17347-17353(2001).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2 AND SER-4, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Serine/threonine protein kinase that plays a role in a
CC variety of different signaling pathways including cytoskeleton
CC regulation, cell migration, or cell cycle regulation. Plays a role in
CC dendrite spine morphogenesis as well as synapse formation and
CC plasticity. Acts as a downstream effector of the small GTPases CDC42
CC and RAC1. Activation by the binding of active CDC42 and RAC1 results in
CC a conformational change and a subsequent autophosphorylation on several
CC serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and
CC activates the downstream target MAPKAPK5, a regulator of F-actin
CC polymerization and cell migration. Additionally, phosphorylates
CC TNNI3/troponin I to modulate calcium sensitivity and relaxation
CC kinetics of thin myofilaments. May also be involved in early neuronal
CC development (PubMed:12890786). In hippocampal neurons, necessary for
CC the formation of dendritic spines and excitatory synapses; this
CC function is dependent on kinase activity and may be exerted by the
CC regulation of actomyosin contractility through the phosphorylation of
CC myosin II regulatory light chain (MLC) (By similarity).
CC {ECO:0000250|UniProtKB:Q61036, ECO:0000269|PubMed:12890786}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC -!- ACTIVITY REGULATION: Activated by binding small G proteins. Binding of
CC GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers
CC from the autoinhibited dimer, enables phosphorylation of Thr-421 and
CC allows the kinase domain to adopt an active structure (By similarity).
CC {ECO:0000250}.
CC -!- SUBUNIT: Interacts tightly with GTP-bound but not GDP-bound CDC42/p21
CC and RAC1. Shows highly specific binding to the SH3 domains of
CC phospholipase C-gamma and of adapter protein NCK. Interacts with the C-
CC terminal of APP. Interacts with ARHGEF6 and ARHGEF7 (By similarity).
CC Interacts with GIT1 and GIT2 (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:O75914}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Detected at high levels in the brain and at low
CC levels in the testis. {ECO:0000269|PubMed:12890786}.
CC -!- DEVELOPMENTAL STAGE: Found in the embryonic CNS with little expression
CC elsewhere.
CC -!- PTM: Autophosphorylated when activated by CDC42/p21.
CC {ECO:0000269|PubMed:11278486}.
CC -!- PTM: Neddylated. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. STE Ser/Thr
CC protein kinase family. STE20 subfamily. {ECO:0000305}.
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DR EMBL; U33314; AAC52268.1; -; mRNA.
DR PIR; A57597; A57597.
DR RefSeq; NP_062083.1; NM_019210.1.
DR RefSeq; XP_006257401.1; XM_006257339.3.
DR AlphaFoldDB; Q62829; -.
DR SMR; Q62829; -.
DR BioGRID; 248080; 2.
DR MINT; Q62829; -.
DR STRING; 10116.ENSRNOP00000006459; -.
DR iPTMnet; Q62829; -.
DR PhosphoSitePlus; Q62829; -.
DR jPOST; Q62829; -.
DR PaxDb; 10116-ENSRNOP00000006459; -.
DR Ensembl; ENSRNOT00000006459.6; ENSRNOP00000006459.4; ENSRNOG00000004676.8.
DR Ensembl; ENSRNOT00055043349; ENSRNOP00055035354; ENSRNOG00055025067.
DR Ensembl; ENSRNOT00060033310; ENSRNOP00060027261; ENSRNOG00060019042.
DR Ensembl; ENSRNOT00065045719; ENSRNOP00065037491; ENSRNOG00065026400.
DR GeneID; 29433; -.
DR KEGG; rno:29433; -.
DR AGR; RGD:3251; -.
DR CTD; 5063; -.
DR RGD; 3251; Pak3.
DR eggNOG; KOG0578; Eukaryota.
DR GeneTree; ENSGT00950000182988; -.
DR HOGENOM; CLU_000288_26_6_1; -.
DR InParanoid; Q62829; -.
DR OrthoDB; 460351at2759; -.
DR BRENDA; 2.7.11.1; 5301.
DR Reactome; R-RNO-202433; Generation of second messenger molecules.
DR Reactome; R-RNO-389359; CD28 dependent Vav1 pathway.
DR Reactome; R-RNO-3928664; Ephrin signaling.
DR Reactome; R-RNO-399954; Sema3A PAK dependent Axon repulsion.
DR Reactome; R-RNO-5218920; VEGFR2 mediated vascular permeability.
DR Reactome; R-RNO-5621575; CD209 (DC-SIGN) signaling.
DR Reactome; R-RNO-5627123; RHO GTPases activate PAKs.
DR Reactome; R-RNO-5687128; MAPK6/MAPK4 signaling.
DR Reactome; R-RNO-9013149; RAC1 GTPase cycle.
DR Reactome; R-RNO-9013420; RHOU GTPase cycle.
DR PRO; PR:Q62829; -.
DR Proteomes; UP000002494; Chromosome X.
DR Bgee; ENSRNOG00000004676; Expressed in Ammon's horn and 7 other cell types or tissues.
DR Genevisible; Q62829; RN.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005768; C:endosome; IDA:RGD.
DR GO; GO:0098978; C:glutamatergic synapse; ISO:RGD.
DR GO; GO:0014069; C:postsynaptic density; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0051020; F:GTPase binding; IDA:RGD.
DR GO; GO:0004708; F:MAP kinase kinase activity; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; IDA:RGD.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:RGD.
DR GO; GO:0017124; F:SH3 domain binding; IEA:UniProtKB-KW.
DR GO; GO:0031267; F:small GTPase binding; ISO:RGD.
DR GO; GO:0007409; P:axonogenesis; ISS:UniProtKB.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; ISO:RGD.
DR GO; GO:0016358; P:dendrite development; ISS:UniProtKB.
DR GO; GO:0060996; P:dendritic spine development; ISO:RGD.
DR GO; GO:0060997; P:dendritic spine morphogenesis; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR GO; GO:0061003; P:positive regulation of dendritic spine morphogenesis; IMP:RGD.
DR GO; GO:2000573; P:positive regulation of DNA biosynthetic process; IMP:RGD.
DR GO; GO:0010763; P:positive regulation of fibroblast migration; IMP:RGD.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:RGD.
DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; IMP:RGD.
DR GO; GO:0030833; P:regulation of actin filament polymerization; ISS:UniProtKB.
DR GO; GO:0050770; P:regulation of axonogenesis; IBA:GO_Central.
DR GO; GO:0043408; P:regulation of MAPK cascade; IBA:GO_Central.
DR GO; GO:0010975; P:regulation of neuron projection development; IMP:RGD.
DR GO; GO:0099175; P:regulation of postsynapse organization; ISO:RGD.
DR CDD; cd01093; CRIB_PAK_like; 1.
DR CDD; cd06656; STKc_PAK3; 1.
DR Gene3D; 3.90.810.10; CRIB domain; 1.
DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
DR InterPro; IPR000095; CRIB_dom.
DR InterPro; IPR036936; CRIB_dom_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR033923; PAK_BD.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR035063; STK_PAK3.
DR PANTHER; PTHR48015; SERINE/THREONINE-PROTEIN KINASE TAO; 1.
DR PANTHER; PTHR48015:SF30; SERINE_THREONINE-PROTEIN KINASE PAK 3; 1.
DR Pfam; PF00786; PBD; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00285; PBD; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR PROSITE; PS50108; CRIB; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Allosteric enzyme; ATP-binding; Cytoplasm; Developmental protein;
KW Direct protein sequencing; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; SH3-binding; Transferase; Ubl conjugation.
FT CHAIN 1..544
FT /note="Serine/threonine-protein kinase PAK 3"
FT /id="PRO_0000086473"
FT DOMAIN 70..83
FT /note="CRIB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00057"
FT DOMAIN 268..519
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..73
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 65..135
FT /note="Autoregulatory region"
FT /evidence="ECO:0000250"
FT REGION 65..108
FT /note="GTPase-binding"
FT /evidence="ECO:0000250"
FT REGION 84..267
FT /note="Linker"
FT REGION 156..197
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 213..248
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 18..32
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 56..73
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 169..186
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 387
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 274..282
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 297
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT MOD_RES 2
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 4
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 50
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11278486"
FT MOD_RES 139
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11278486"
FT MOD_RES 171
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q61036"
FT MOD_RES 421
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11278486"
FT MUTAGEN 297
FT /note="K->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:12890786"
FT MUTAGEN 421
FT /note="T->E: Constitutively active."
FT /evidence="ECO:0000269|PubMed:12890786"
SQ SEQUENCE 544 AA; 60711 MW; 7B940FC204A2B48B CRC64;
MSDSLDNEEK PPAPPLRMNS NNRDSSALNH SSKPLPMAPE EKNKKARLRS IFPGGGDKTN
KKKEKERPEI SLPSDFEHTI HVGFDAVTGE FTGIPEQWAR LLQTSNITKL EQKKNPQAVL
DVLKFYDSKE TVNNQKYMSF TSGDKSAHGY IAAHQSNTKT ASEPPLAPPV SEEEDEEEEE
EEDDNEPPPV IAPRPEHTKS IYTRSVVESI ASPAAPNKEA TPPSAENANS STLYRNTDRQ
RKKSKMTDEE ILEKLRSIVS VGDPKKKYTR FEKIGQGASG TVYTALDIAT GQEVAIKQMN
LQQQPKKELI INEILVMREN KNPNIVNYLD SYLVGDELWV VMEYLAGGSL TDVVTETCMD
EGQIAAVCRE CLQALDFLHS NQVIHRDIKS DNILLGMDGS VKLTDFGFCA QITPEQSKRS
TMVGTPYWMA PEVVTRKAYG PKVDIWSLGI MAIEMVEGEP PYLNENPLRA LYLIATNGTP
ELQNPERLSA VFRDFLNRCL EMDVDRRGSA KELLQHPFLK LAKPLSSLTP LILAAKEAIK
NSSR
//
