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Protein

Activated CDC42 kinase 1

Gene

Tnk2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR.2 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation
ATP + a protein = ADP + a phosphoprotein.

Cofactori

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei158ATP1
Active sitei252Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi132 – 140ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Endocytosis

Keywords - Ligandi

ATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Activated CDC42 kinase 1 (EC:2.7.10.2, EC:2.7.11.1)
Short name:
ACK-1
Alternative name(s):
Non-receptor protein tyrosine kinase Ack
Tyrosine kinase non-receptor protein 2
Gene namesi
Name:Tnk2
Synonyms:Ack1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1858308. Tnk2.

Subcellular locationi

GO - Cellular componenti

  • adherens junction Source: UniProtKB-SubCell
  • axon Source: MGI
  • clathrin-coated pit Source: MGI
  • clathrin-coated vesicle Source: MGI
  • cytoplasm Source: UniProtKB
  • cytoplasmic vesicle membrane Source: UniProtKB-SubCell
  • dendrite Source: MGI
  • endosome Source: UniProtKB
  • extrinsic component of cytoplasmic side of plasma membrane Source: GO_Central
  • Grb2-EGFR complex Source: MGI
  • growth cone Source: MGI
  • membrane Source: MGI
  • neuronal cell body Source: MGI
  • nucleus Source: UniProtKB
  • plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cell membrane, Coated pit, Cytoplasmic vesicle, Endosome, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi158K → A: Loss of kinase activity. 1 Publication1
Mutagenesisi424W → K: Increase in autophosphorylation activity. 1 Publication1
Mutagenesisi464H → D: Loss of CDC42-binding and impairment of autophosphorylation. 1 Publication1
Mutagenesisi650Y → A: Loss of interaction with NEDD4 and drastic reduction in its ubiquitination. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL2079848.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000880591 – 1055Activated CDC42 kinase 1Add BLAST1055

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei113PhosphothreonineCombined sources1
Modified residuei284Phosphotyrosine; by SRC and autocatalysisBy similarity1
Modified residuei533Phosphotyrosine1 Publication1
Modified residuei842PhosphotyrosineBy similarity1
Modified residuei854Omega-N-methylarginineCombined sources1
Modified residuei874PhosphotyrosineBy similarity1
Modified residuei887PhosphotyrosineBy similarity1
Modified residuei896PhosphoserineBy similarity1
Isoform 2 (identifier: O54967-2)
Modified residuei518PhosphotyrosineCombined sources1
Isoform 3 (identifier: O54967-3)
Modified residuei518PhosphotyrosineCombined sources1

Post-translational modificationi

Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-533 is required for interaction with SRC and is observed during association with clathrin-coated pits (By similarity).By similarity
Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced by EGF and is lysosome-dependent.1 Publication

Keywords - PTMi

Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiO54967.
PaxDbiO54967.
PeptideAtlasiO54967.
PRIDEiO54967.

PTM databases

iPTMnetiO54967.
PhosphoSitePlusiO54967.

Expressioni

Tissue specificityi

Ubiquitously present in all tissues tested. Highly expressed in the adult central nervous system (CNS); hippocampus, neocortex, and cerebellum, both at dendritic spines and presynaptic axon terminals. Levels are strongly increased during enhanced neural activity.3 Publications

Developmental stagei

Highly expressed at E14-E16 in the forebrain, in the proliferative ventricular zone of the neocortex and hippocampus, and in the cortical and hippocampal plates. Also observed in the septal area, the ganglionic eminence, and in the dorsal thalamus and hypothalamus. In the hindbrain, expressed in many nuclei in the brain stem and in the cerebellar anlage, external granule cell layer, in Purkinje cells and the deep cerebellar nuclei.2 Publications

Inductioni

Down-regulated by EGF.1 Publication

Gene expression databases

BgeeiENSMUSG00000022791.
CleanExiMM_TNK2.

Interactioni

Subunit structurei

Homodimer. Interacts with CSPG4 (activated). Interacts with MERTK (activated); stimulates autophosphorylation. May interact (phosphorylated) with HSP90AB1; maintains kinase activity. Interacts with NPHP1. Interacts with SNX9 (via SH3 domain). Interacts with SRC (via SH2 and SH3 domain). Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas. Interacts with BCAR1/p130cas via SH3 domains. Forms complexes with GRB2 and numerous receptor tyrosine kinases (RTK) including LTK, AXL or PDGFRL, in which GRB2 promotes RTK recruitment by TNK2 (By similarity). Interacts with CDC42. Interacts with EGFR, and this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts (via kinase domain) with AKT1. Interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote association with NEDD4.By similarity4 Publications

GO - Molecular functioni

  • epidermal growth factor receptor binding Source: MGI
  • receptor binding Source: GO_Central
  • WW domain binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi206174. 6 interactors.
DIPiDIP-57223N.
IntActiO54967. 1 interactor.
STRINGi10090.ENSMUSP00000110777.

Chemistry databases

BindingDBiO54967.

Structurei

3D structure databases

ProteinModelPortaliO54967.
SMRiO54967.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini126 – 385Protein kinasePROSITE-ProRule annotationAdd BLAST260
Domaini386 – 448SH3PROSITE-ProRule annotationAdd BLAST63
Domaini454 – 466CRIBAdd BLAST13
Domaini973 – 1013UBAAdd BLAST41

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 110SAM-like domainAdd BLAST110
Regioni638 – 667Required for interaction with SRCAdd BLAST30
Regioni647 – 650Required for interaction with NEDD41 Publication4
Regioni748 – 891EBD domainAdd BLAST144

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi517 – 950Pro-richAdd BLAST434

Domaini

The EBD (EGFR-binding domain) domain is necessary for interaction with EGFR.
The SAM-like domain is necessary for NEDD4-mediated ubiquitination. Promotes membrane localization and dimerization to allow for autophosphorylation.
The UBA domain binds both poly- and mono-ubiquitin.

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family.PROSITE-ProRule annotation
Contains 1 CRIB domain.Curated
Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 SH3 domain.PROSITE-ProRule annotation
Contains 1 UBA domain.Curated

Keywords - Domaini

SH3 domain

Phylogenomic databases

eggNOGiKOG0199. Eukaryota.
ENOG410XPRC. LUCA.
HOGENOMiHOG000168225.
HOVERGENiHBG100429.
InParanoidiO54967.
KOiK08886.
PhylomeDBiO54967.

Family and domain databases

Gene3Di4.10.680.10. 1 hit.
InterProiIPR015116. Cdc42_binding_dom-like.
IPR011009. Kinase-like_dom.
IPR021619. Mig-6.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR001452. SH3_domain.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR009060. UBA-like.
[Graphical view]
PfamiPF09027. GTPase_binding. 1 hit.
PF11555. Inhibitor_Mig-6. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF14604. SH3_9. 1 hit.
[Graphical view]
PRINTSiPR00109. TYRKINASE.
SMARTiSM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF46934. SSF46934. 1 hit.
SSF50044. SSF50044. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O54967-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MQPEEGTGWL LELLSEVQLQ QYFLRLRDDL NITRLSHFEY VKNEDLEKIG
60 70 80 90 100
MGRPGQRRLW EAVKRRKAMC KRKSWMSKVF SGKRLEAEFP SQHSQSTFRK
110 120 130 140 150
PSPTPGSLPG EGTLQSLTCL IGEKDLRLLE KLGDGSFGVV RRGEWDAPAG
160 170 180 190 200
KTVSVAVKCL KPDVLSQPEA MDDFIREVNA MHSLDHRNLI RLYGVVLTLP
210 220 230 240 250
MKMVTELAPL GSLLDRLRKH QGHFLLGTLS RYAVQVAEGM AYLESKRFIH
260 270 280 290 300
RDLAARNLLL ATRDLVKIGD FGLMRALPQN DDHYVMQEHR KVPFAWCAPE
310 320 330 340 350
SLKTRTFSHA SDTWMFGVTL WEMFTYGQEP WIGLNGSQIL HKIDKEGERL
360 370 380 390 400
PRPEDCPQDI YNVMVQCWAH KPEDRPTFVA LRDFLLEAQP TDMRALQDFE
410 420 430 440 450
EPDKLHIQMN DVITVIEGRA ENYWWRGQNT RTLCVGPFPR NVVTSVAGLS
460 470 480 490 500
AQDISQPLQN SFIHTGHGDS DPRHCWGFPD RIDELYLGNP MDPPDLLSVE
510 520 530 540 550
LSTSRPTQHL GRVKREPPPR PPQPAIFTQK TTYDPVSEDP DPLSSDFKRL
560 570 580 590 600
GLRKPALPRG LWLAKPSARV PGTKADRSSG GEVTLIDFGE EPVVPTPRPC
610 620 630 640 650
APSLAQLAMD ACSLLDKTPP QSPTRALPRP LHPTPVVDWD ARPLPPPPAY
660 670 680 690 700
DDVAQDEDDF EVCSINSTLV GAGLPAGPSQ GETNYAFVPE QAQMPPALED
710 720 730 740 750
NLFLPPQGGG KPPSSVQTAE IFQALQQECM RQLQVPTGQL TPSPTPGGDD
760 770 780 790 800
KPQVPPRVPI PPRPTRPRVE LSPAPSGEEE TSRWPGPASP PRVPPREPLS
810 820 830 840 850
PQGSRTPSPL VPPGSSPLPH RLSSSPGKTM PTTQSFASDP KYATPQVIQA
860 870 880 890 900
PGPRAGPCIL PIVRDGRKVS STHYYLLPER PPYLERYQRF LREAQSPEEP
910 920 930 940 950
AALPVPPLLP PPSTPAPAAP TATVRPMPQA APDPKANFST NNSNPGARPP
960 970 980 990 1000
SLRAAARLPQ RGCPGDGQEA ARPADKVQML QAMVHGVTTE ECQAALQSHS
1010 1020 1030 1040 1050
WSVQRAAQYL KVEQLFGLGL RPRVECHKVL EMFDWNLEQA GCHLLGSCGP

AHHKR
Length:1,055
Mass (Da):116,975
Last modified:December 4, 2007 - v2
Checksum:i4A029C67C350B89A
GO
Isoform 2 (identifier: O54967-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     515-531: REPPPRPPQPAIFTQKT → KP
     980-1011: Missing.

Note: No experimental confirmation available.Combined sources
Show »
Length:1,008
Mass (Da):111,704
Checksum:i09718C0B88D4F2D1
GO
Isoform 3 (identifier: O54967-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     515-531: REPPPRPPQPAIFTQKT → KP

Show »
Length:1,040
Mass (Da):115,258
Checksum:iA2401DAFB05715E0
GO

Sequence cautioni

The sequence AAH31168 differs from that shown. Contaminating sequence. Sequence of unknown origin in the N-terminal part.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti57 – 58RR → SG in AAC04786 (Ref. 2) Curated2
Sequence conflicti531T → P in ABG46266 (PubMed:16777958).Curated1
Sequence conflicti574K → E in ABG46266 (PubMed:16777958).Curated1
Sequence conflicti649A → V in AAC04786 (Ref. 2) Curated1
Sequence conflicti818L → V in BAC40063 (PubMed:15489334).Curated1
Sequence conflicti955A → T in AAH52421 (Ref. 2) Curated1
Sequence conflicti955A → T in BAC40063 (PubMed:15489334).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_008657515 – 531REPPP…FTQKT → KP in isoform 2 and isoform 3. 2 PublicationsAdd BLAST17
Alternative sequenceiVSP_008658980 – 1011Missing in isoform 2. 1 PublicationAdd BLAST32

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
DQ666696 mRNA. Translation: ABG46266.1.
AF037260 mRNA. Translation: AAC04786.1.
BC031168 mRNA. Translation: AAH31168.1. Sequence problems.
BC052421 mRNA. Translation: AAH52421.1.
AK087965 mRNA. Translation: BAC40063.1.
CCDSiCCDS37313.1. [O54967-1]
CCDS49828.1. [O54967-2]
RefSeqiNP_001103617.1. NM_001110147.1.
NP_001276372.1. NM_001289443.1.
NP_058068.2. NM_016788.3.
UniGeneiMm.251115.

Genome annotation databases

GeneIDi51789.
KEGGimmu:51789.
UCSCiuc007yzc.2. mouse. [O54967-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
DQ666696 mRNA. Translation: ABG46266.1.
AF037260 mRNA. Translation: AAC04786.1.
BC031168 mRNA. Translation: AAH31168.1. Sequence problems.
BC052421 mRNA. Translation: AAH52421.1.
AK087965 mRNA. Translation: BAC40063.1.
CCDSiCCDS37313.1. [O54967-1]
CCDS49828.1. [O54967-2]
RefSeqiNP_001103617.1. NM_001110147.1.
NP_001276372.1. NM_001289443.1.
NP_058068.2. NM_016788.3.
UniGeneiMm.251115.

3D structure databases

ProteinModelPortaliO54967.
SMRiO54967.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi206174. 6 interactors.
DIPiDIP-57223N.
IntActiO54967. 1 interactor.
STRINGi10090.ENSMUSP00000110777.

Chemistry databases

BindingDBiO54967.
ChEMBLiCHEMBL2079848.

PTM databases

iPTMnetiO54967.
PhosphoSitePlusiO54967.

Proteomic databases

MaxQBiO54967.
PaxDbiO54967.
PeptideAtlasiO54967.
PRIDEiO54967.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi51789.
KEGGimmu:51789.
UCSCiuc007yzc.2. mouse. [O54967-2]

Organism-specific databases

CTDi10188.
MGIiMGI:1858308. Tnk2.

Phylogenomic databases

eggNOGiKOG0199. Eukaryota.
ENOG410XPRC. LUCA.
HOGENOMiHOG000168225.
HOVERGENiHBG100429.
InParanoidiO54967.
KOiK08886.
PhylomeDBiO54967.

Miscellaneous databases

ChiTaRSiTnk2. mouse.
PROiO54967.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000022791.
CleanExiMM_TNK2.

Family and domain databases

Gene3Di4.10.680.10. 1 hit.
InterProiIPR015116. Cdc42_binding_dom-like.
IPR011009. Kinase-like_dom.
IPR021619. Mig-6.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR001452. SH3_domain.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR009060. UBA-like.
[Graphical view]
PfamiPF09027. GTPase_binding. 1 hit.
PF11555. Inhibitor_Mig-6. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF14604. SH3_9. 1 hit.
[Graphical view]
PRINTSiPR00109. TYRKINASE.
SMARTiSM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF46934. SSF46934. 1 hit.
SSF50044. SSF50044. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50002. SH3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiACK1_MOUSE
AccessioniPrimary (citable) accession number: O54967
Secondary accession number(s): Q0Z844, Q8C2U0, Q8K0K4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 24, 2003
Last sequence update: December 4, 2007
Last modified: November 30, 2016
This is version 155 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.