ACK1_BOVIN
ID ACK1_BOVIN Reviewed; 1039 AA.
AC Q17R13; O02742;
DT 04-DEC-2007, integrated into UniProtKB/Swiss-Prot.
DT 25-JUL-2006, sequence version 1.
DT 03-AUG-2022, entry version 120.
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=Activated CDC42 kinase 2;
DE AltName: Full=Tyrosine kinase non-receptor protein 2;
GN Name=TNK2 {ECO:0000250|UniProtKB:Q07912};
GN Synonyms=ACK1 {ECO:0000250|UniProtKB:Q07912}, ACK2;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), CATALYTIC ACTIVITY, AND INTERACTION
RP WITH CDC42.
RC TISSUE=Brain;
RX PubMed=9312079; DOI=10.1074/jbc.272.40.24819;
RA Yang W., Cerione R.A.;
RT "Cloning and characterization of a novel Cdc42-associated tyrosine kinase,
RT ACK-2, from bovine brain.";
RL J. Biol. Chem. 272:24819-24824(1997).
RN [2] {ECO:0000312|EMBL:AAI18082.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=Hereford {ECO:0000312|EMBL:AAI18082.1};
RC TISSUE=Hypothalamus {ECO:0000312|EMBL:AAI18082.1};
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (JUN-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION, INTERACTION WITH SNX9 AND EGFR, IDENTIFICATION IN A COMPLEX WITH
RP SNX9 AND CLATHRIN HEAVY CHAIN, AND MUTAGENESIS OF LYS-158.
RX PubMed=11799118; DOI=10.1074/jbc.m110329200;
RA Lin Q., Lo C.G., Cerione R.A., Yang W.;
RT "The Cdc42 target ACK2 interacts with sorting nexin 9 (SH3PX1) to regulate
RT epidermal growth factor receptor degradation.";
RL J. Biol. Chem. 277:10134-10138(2002).
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, ECO:0000269|PubMed:11799118}.
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, ECO:0000269|PubMed:9312079};
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 Evidence={ECO:0000269|PubMed:9312079};
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; Evidence={ECO:0000269|PubMed:9312079};
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 SRC
CC (via SH2 and SH3 domain). Interacts (via kinase domain) with AKT1. Part
CC of a collagen stimulated complex involved in cell migration composed of
CC CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with BCAR1/p130cas via
CC SH3 domains. Forms complexes with GRB2 and numerous receptor tyrosine
CC kinases (RTK) including LTK, AXL or PDGFRL, in which GRB2 promotes RTK
CC recruitment by TNK2. Interacts with NEDD4 (via WW3 domain). NEDD4L and
CC EGF promote association with NEDD4 (By similarity). Interacts with
CC EGFR, and this interaction is dependent on EGF stimulation and kinase
CC activity of EGFR. Interacts with SNX9 (via SH3 domain). {ECO:0000250,
CC ECO:0000269|PubMed:11799118, ECO:0000269|PubMed:9312079}.
CC -!- INTERACTION:
CC Q17R13; Q9Y5X1: SNX9; Xeno; NbExp=5; IntAct=EBI-457220, EBI-77848;
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 -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q17R13-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q17R13-2; Sequence=VSP_038165, VSP_038166, VSP_038167;
CC -!- TISSUE SPECIFICITY: Expressed in brain and skeletal muscle. Weakly
CC expressed in pancreas, heart, placenta and lung.
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}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC05310.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; U96722; AAC05310.1; ALT_FRAME; mRNA.
DR EMBL; BC118081; AAI18082.1; -; mRNA.
DR RefSeq; NP_776310.2; NM_173885.3. [Q17R13-1]
DR AlphaFoldDB; Q17R13; -.
DR SMR; Q17R13; -.
DR IntAct; Q17R13; 4.
DR STRING; 9913.ENSBTAP00000043771; -.
DR PaxDb; Q17R13; -.
DR PRIDE; Q17R13; -.
DR GeneID; 280710; -.
DR KEGG; bta:280710; -.
DR CTD; 10188; -.
DR eggNOG; KOG0199; Eukaryota.
DR InParanoid; Q17R13; -.
DR OrthoDB; 1008736at2759; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0005912; C:adherens junction; IEA:UniProtKB-SubCell.
DR GO; GO:0005905; C:clathrin-coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0030136; C:clathrin-coated vesicle; IEA:UniProtKB-SubCell.
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:0005768; C:endosome; ISS:UniProtKB.
DR GO; GO:0031234; C:extrinsic component of cytoplasmic side of plasma membrane; IBA:GO_Central.
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: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; IEA:InterPro.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
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: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 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Cell junction; Cell membrane;
KW Coated pit; Cytoplasm; Cytoplasmic vesicle; Endocytosis; Endosome; Kinase;
KW Magnesium; Membrane; Metal-binding; Methylation; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; SH3 domain; Transferase;
KW Tyrosine-protein kinase; Ubl conjugation.
FT CHAIN 1..1039
FT /note="Activated CDC42 kinase 1"
FT /id="PRO_0000312829"
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 957..997
FT /note="UBA"
FT /evidence="ECO:0000255"
FT REGION 1..110
FT /note="SAM-like domain"
FT /evidence="ECO:0000250"
FT REGION 90..113
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 503..532
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 622..651
FT /note="Required for interaction with SRC"
FT /evidence="ECO:0000250"
FT REGION 631..634
FT /note="Required for interaction with NEDD4"
FT /evidence="ECO:0000250"
FT REGION 682..701
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 719..839
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 732..875
FT /note="EBD domain"
FT /evidence="ECO:0000250"
FT REGION 878..957
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 94..113
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 516..532
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 723..753
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 771..804
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 805..826
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 883..906
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 918..934
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 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 723
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT MOD_RES 826
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT MOD_RES 838
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:O54967"
FT MOD_RES 858
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT MOD_RES 871
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT MOD_RES 880
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q07912"
FT VAR_SEQ 514
FT /note="K -> KREPPPRPPQPAIFTQ (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9312079"
FT /id="VSP_038165"
FT VAR_SEQ 814..856
FT /note="MPTTQSFASDPKYATPQVIQAPGPRAGPCILPIVRDGKKVSST -> ENYVQ
FT NFKNLTAHHPPWRDQDTGTGSSRGPTVLSPECGRETPF (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9312079"
FT /id="VSP_038166"
FT VAR_SEQ 857..1039
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9312079"
FT /id="VSP_038167"
FT MUTAGEN 158
FT /note="K->R: Abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:11799118"
FT CONFLICT 203
FT /note="T -> M (in Ref. 1; AAC05310)"
FT /evidence="ECO:0000305"
FT CONFLICT 534
FT /note="R -> K (in Ref. 1; AAC05310)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1039 AA; 114868 MW; E7834771D76F8472 CRC64;
MQPEEGTGWL LELLSEVQLQ QYFLRLRDDL NVTRLSHFEY VKNEDLEKIG MGRPGQRRLW
EAVKRRKAMC KRKSWMSKVF SGKRLEAEFP PHHSQSTFRK TSPTPGGSAG EGSLQSLTCL
IGEKDLHLFE KLGDGSFGVV RRGEWDAPSG KTVSVAVKCL KPDVLSQPEA MDDFIREVNA
MHSLDHRNLI RLYGVVLTPP MKTVTELAPL GSLLDRLRKH QGHFLLGTLS RYAVQVAEGM
GYLEAKRFIH RDLAARNLLL ATRDLVKIGD FGLMRALPQN DDHYVMQEHR KVPFAWCAPE
SLKTRTFSHA SDTWMFGVTL WEMFTYGQEP WIGLNGSQIL HKIDKEGERL PRPEDCPQDI
YNVMVQCWAH KPEDRPTFVA LRDFLLEAQP TDMRALQDFE EPDKLHIQMN DVITVIEGRA
ENYWWRGQNT RTLCVGPFPR NVVTSVAGLS AQDISQPLQN SFIHTGHGDS DPRHCWGFPD
KIDELYLGNP MDPPDLLSVE LSTSRPTQHL GRVKKPTYDP VSEDQDPLSS DFKRLGLRKP
GLPRGLWLAK PSARVPGTKA GRGGGEVTLI DFGEEPVVPA PRPCAPSLAQ LAMDACSLLD
KTPPQSPTRA LPRPLHPTPV VDWDARPLPP PPAYDDVAQD EDDFEVCSIN STLVGAGVSA
EPSQGETNYA FVPEPARLLP PLEDNLFLPP QSGGKPPNSA QTAEIFQALQ QECMRQLQVP
PGSLVPSPSP GGDDKPQVPP RVPIPPRPTR SRGELSPVPP GEEEMGRWPG PASPPRVPPR
EPLSPQGSRT PSPLVPPGSS PLPPRLSSSP GKTMPTTQSF ASDPKYATPQ VIQAPGPRAG
PCILPIVRDG KKVSSTHYYL LPERPPYLER YQRFLHEAQS PRGPDPTPIP LLLPPPSTPA
PAAPTATVRP MPQAAPDPKA NFSSNNSNPG ARPSSLRATA RLPQRGYPGD GPEAGRPADK
IQMLQAMVHG VTTEECQAAL QSHSWSVQRA AQYLKVEQLF GLGLRPRGEC HNVLEMFDWN
LEQAGCHLLG SCGPAHHKR
