ACK1_RAT
ID ACK1_RAT Reviewed; 1040 AA.
AC Q5U2X5;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 07-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 125.
DE RecName: Full=Activated CDC42 kinase 1;
DE Short=ACK-1;
DE EC=2.7.10.2;
DE EC=2.7.11.1;
DE AltName: Full=Tyrosine kinase non-receptor protein 2;
GN Name=Tnk2 {ECO:0000250|UniProtKB:Q07912};
GN Synonyms=Ack1 {ECO:0000250|UniProtKB:Q07912};
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] {ECO:0000312|EMBL:AAH85825.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney {ECO:0000312|EMBL:AAH85825.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
CC -!- FUNCTION: Non-receptor tyrosine-protein and serine/threonine-protein
CC kinase that is implicated in cell spreading and migration, cell
CC survival, cell growth and proliferation. Transduces extracellular
CC signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR,
CC MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated
CC endocytosis through binding to epidermal growth factor receptor (EGFR)
CC and clathrin. Binds to both poly- and mono-ubiquitin and regulates
CC ligand-induced degradation of EGFR, thereby contributing to the
CC accumulation of EGFR at the limiting membrane of early endosomes.
CC Downstream effector of CDC42 which mediates CDC42-dependent cell
CC migration via phosphorylation of BCAR1. May be involved both in adult
CC synaptic function and plasticity and in brain development. Activates
CC AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267'
CC and 'Tyr-363', thereby promoting its recruitment to androgen-responsive
CC enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates
CC MCF2, thereby enhancing its activity as a guanine nucleotide exchange
CC factor (GEF) toward Rho family proteins. Contributes to the control of
CC AXL receptor levels. Confers metastatic properties on cancer cells and
CC promotes tumor growth by negatively regulating tumor suppressor such as
CC WWOX and positively regulating pro-survival factors such as AKT1 and AR
CC (By similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000250|UniProtKB:Q07912, ECO:0000255|PROSITE-
CC ProRule:PRU10028};
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 Evidence={ECO:0000250|UniProtKB:Q07912};
CC -!- SUBUNIT: Homodimer. Interacts with CDC42. Interacts with CSPG4
CC (activated). Interacts with MERTK (activated); stimulates
CC autophosphorylation. May interact (phosphorylated) with HSP90AB1;
CC maintains kinase activity. Interacts with NPHP1. Interacts with SNX9
CC (via SH3 domain). Interacts with SRC (via SH2 and SH3 domain).
CC Interacts with EGFR, and this interaction is dependent on EGF
CC stimulation and kinase activity of EGFR. Interacts (via kinase domain)
CC with AKT1. Part of a collagen stimulated complex involved in cell
CC migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts
CC with BCAR1/p130cas via SH3 domains. Forms complexes with GRB2 and
CC numerous receptor tyrosine kinases (RTK) including LTK, AXL or PDGFRL,
CC in which GRB2 promotes RTK recruitment by TNK2. Interacts with NEDD4
CC (via WW3 domain). NEDD4L and EGF promote association with NEDD4 (By
CC similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:O54967}.
CC Nucleus {ECO:0000250|UniProtKB:O54967}. Endosome
CC {ECO:0000250|UniProtKB:O54967}. Cell junction, adherens junction
CC {ECO:0000250|UniProtKB:O54967}. Cytoplasmic vesicle membrane;
CC Peripheral membrane protein; Cytoplasmic side
CC {ECO:0000250|UniProtKB:Q07912}. Cytoplasmic vesicle, clathrin-coated
CC vesicle {ECO:0000250|UniProtKB:Q07912}. Membrane, clathrin-coated pit
CC {ECO:0000250|UniProtKB:O54967}. Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:O54967}. Note=The Tyr-284 phosphorylated form is
CC found both in the membrane and nucleus. Co-localizes with EGFR on
CC endosomes. Nuclear translocation is CDC42-dependent. Detected in long
CC filamentous cytosolic structures where it co-localizes with CTPS1.
CC {ECO:0000250|UniProtKB:O54967}.
CC -!- DOMAIN: The EBD (EGFR-binding domain) domain is necessary for
CC interaction with EGFR. {ECO:0000250}.
CC -!- DOMAIN: The SAM-like domain is necessary for NEDD4-mediated
CC ubiquitination. Promotes membrane localization and dimerization to
CC allow for autophosphorylation (By similarity). {ECO:0000250}.
CC -!- DOMAIN: The UBA domain binds both poly- and mono-ubiquitin.
CC {ECO:0000250}.
CC -!- PTM: Autophosphorylation regulates kinase activity. Phosphorylation on
CC Tyr-518 is required for interaction with SRC and is observed during
CC association with clathrin-coated pits (By similarity). {ECO:0000250}.
CC -!- PTM: Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced
CC by EGF and is lysosome-dependent (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. {ECO:0000250|UniProtKB:Q07912, ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; BC085825; AAH85825.1; -; mRNA.
DR RefSeq; NP_001008337.1; NM_001008336.1.
DR AlphaFoldDB; Q5U2X5; -.
DR SMR; Q5U2X5; -.
DR BioGRID; 257704; 2.
DR STRING; 10116.ENSRNOP00000002411; -.
DR iPTMnet; Q5U2X5; -.
DR PhosphoSitePlus; Q5U2X5; -.
DR PaxDb; Q5U2X5; -.
DR PRIDE; Q5U2X5; -.
DR GeneID; 303882; -.
DR KEGG; rno:303882; -.
DR CTD; 10188; -.
DR RGD; 1305957; Tnk2.
DR eggNOG; KOG0199; Eukaryota.
DR InParanoid; Q5U2X5; -.
DR OrthoDB; 1008736at2759; -.
DR PRO; PR:Q5U2X5; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005912; C:adherens junction; IEA:UniProtKB-SubCell.
DR GO; GO:0030424; C:axon; ISO:RGD.
DR GO; GO:0005905; C:clathrin-coated pit; ISO:RGD.
DR GO; GO:0030136; C:clathrin-coated vesicle; ISO:RGD.
DR GO; GO:0097268; C:cytoophidium; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0030425; C:dendrite; ISO:RGD.
DR GO; GO:0005768; C:endosome; ISS:UniProtKB.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IBA:GO_Central.
DR GO; GO:0070436; C:Grb2-EGFR complex; ISO:RGD.
DR GO; GO:0030426; C:growth cone; ISO:RGD.
DR GO; GO:0043025; C:neuronal cell body; ISO:RGD.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005154; F:epidermal growth factor receptor binding; ISO:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; ISO:RGD.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:MGI.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:RGD.
DR GO; GO:0050699; F:WW domain binding; ISO:RGD.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0016310; P:phosphorylation; ISS:UniProtKB.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISO:RGD.
DR GO; GO:2000369; P:regulation of clathrin-dependent endocytosis; ISO:RGD.
DR GO; GO:0007286; P:spermatid development; ISO:RGD.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR Gene3D; 4.10.680.10; -; 1.
DR InterPro; IPR030220; Ack1.
DR InterPro; IPR015116; Cdc42-bd-like.
DR InterPro; IPR037085; Cdc42-bd-like_dom_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR021619; Mig-6.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR036028; SH3-like_dom_sf.
DR InterPro; IPR001452; SH3_domain.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR PANTHER; PTHR14254:SF6; PTHR14254:SF6; 1.
DR Pfam; PF09027; GTPase_binding; 1.
DR Pfam; PF11555; Inhibitor_Mig-6; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF14604; SH3_9; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00326; SH3; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF50044; SSF50044; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS50002; SH3; 1.
PE 2: Evidence at transcript level;
KW ATP-binding; Cell junction; Cell membrane; Coated pit; Cytoplasm;
KW Cytoplasmic vesicle; Endocytosis; Endosome; Kinase; Magnesium; Membrane;
KW Metal-binding; Methylation; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; SH3 domain;
KW Transferase; Tyrosine-protein kinase; Ubl conjugation.
FT CHAIN 1..1040
FT /note="Activated CDC42 kinase 1"
FT /id="PRO_0000312830"
FT DOMAIN 126..385
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 388..448
FT /note="SH3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00192"
FT DOMAIN 958..998
FT /note="UBA"
FT /evidence="ECO:0000255"
FT REGION 1..110
FT /note="SAM-like domain"
FT /evidence="ECO:0000250"
FT REGION 86..109
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 505..527
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 623..652
FT /note="Required for interaction with SRC"
FT /evidence="ECO:0000250"
FT REGION 632..635
FT /note="Required for interaction with NEDD4"
FT /evidence="ECO:0000250"
FT REGION 722..824
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 733..876
FT /note="EBD domain"
FT /evidence="ECO:0000250"
FT REGION 881..957
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 733..754
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 772..801
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 803..824
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 885..907
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 919..935
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 252
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P00517,
FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-
FT ProRule:PRU10028"
FT BINDING 132..140
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P00517,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 158
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:O54967,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 113
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:O54967"
FT MOD_RES 284
FT /note="Phosphotyrosine; by SRC and autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT MOD_RES 518
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT MOD_RES 827
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT MOD_RES 839
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:O54967"
FT MOD_RES 859
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT MOD_RES 872
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT MOD_RES 881
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
SQ SEQUENCE 1040 AA; 115068 MW; 0624944919F821F6 CRC64;
MQPEEGTGWL LELLSEVQLQ QYFLRLRDDL NITRLSHFEY VKNEDLEKIG MGRPGQRRLW
EAVKRRKAMC KRKSWMSKVF SGKRQEAEFP SHHSQSTFRK PSPTPGGLAG EGTLQSLTCL
IGEKDLRLLE KLGDGSFGVV RRGEWDAPAG KTVSVAVKCL KPDVLSQPEA MDDFIREVNA
MHSLDHRNLI RLYGVVLTPP MKMVTELAPL GSLLDRLRKH QGHFLLGTLS RYAVQVAEGM
GYLESKRFIH RDLAARNLLL ATRDLVKIGD FGLMRALPQN DGHYVMQEHR KVPFAWCAPE
SLKTRTFSHA SDTWMFGVTL WEMFTYGQEP WIGLNGSQIL HKIDKEGERL PRPEDCPQDI
YNVMVQCWAH KPEDRPTFVA LRDFLLEAQP TDMRALQDFE EPDKLHIQMN DVITVIEGRA
ENYWWRGQNT RTLCVGPFPR NVVTSVAGLS AQDISQPLQN SFIHTGHGDS DPRHCWGFPD
RIDELYLGNP MDPPDLLSVE LSTSRPTQHL GRMKKPTYDP VSEDPDPLSS DFKRLGLRKP
ALPRGLWLAK PSARVPGTKA GRSSGGEVTL IDFGEEPVAP TPRPCAPSLA QLAMDACSLL
DKTPPQSPTR ALPRPLHPTP VVDWDARPLP PPPAYDDVAQ DEDDFEVCSI NSTLVSAGLP
TGPSQGETNY AFVPEQAQLP PALEDNLFLP PQGGGQPPSS AQTAEIFQAL QQECMRQLQV
PTGQLTPSPT PGGDDKPQVP PRVPIPPRPT RPRVGLSPAP LGEEEASRWP GPSSPPRVPP
REPLSPQGSR TPSPLVPPGS SPLPHRLSSS PGKTMPTTQS FASDPKYATP QVIQAPGPRA
GPCILPIVRD GRKVSSTHYY LLPERPPYLE RYQRFLREAQ SPEEPAALPV PPLLPPPSTP
APAAPTATVR PMPQAAPDPK ANFSTNNSNP GAQPPSLRAS ARLPQRGCPG DGQEAARPAD
KVQMLQAMVH GVTTEECQAA LRSHSWSIQR AAQYLKVEQL FGLGLRPRVE CHKVLEMFDW
NLEQAGCHLL GSCGPAHHKR
