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Protein

Activated CDC42 kinase 1

Gene

Tnk2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase, Tyrosine-protein kinase
Biological processEndocytosis
LigandATP-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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:1858308 Tnk2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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

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

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi206174, 7 interactors
DIPiDIP-57223N
IntActiO54967, 3 interactors
MINTiO54967
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
Domaini388 – 448SH3PROSITE-ProRule annotationAdd BLAST61
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

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
InterProiView protein in InterPro
IPR030220 Ack1
IPR037085 Cdc42-bd-like_dom_sf
IPR015116 Cdc42_binding_dom-like
IPR011009 Kinase-like_dom_sf
IPR021619 Mig-6
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR009060 UBA-like_sf
PANTHERiPTHR14254:SF4 PTHR14254:SF4, 1 hit
PfamiView protein in Pfam
PF09027 GTPase_binding, 1 hit
PF11555 Inhibitor_Mig-6, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF14604 SH3_9, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00326 SH3, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF46934 SSF46934, 1 hit
SSF50044 SSF50044, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit
PS50002 SH3, 1 hit

Sequences (3+)i

Sequence statusi: Complete.

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

This entry has 3 described isoforms and 11 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 11 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
G3X9X7G3X9X7_MOUSE
Activated CDC42 kinase 1
Tnk2 mCG_130126
1,055Annotation score:
D3Z3U6D3Z3U6_MOUSE
Activated CDC42 kinase 1
Tnk2
1,040Annotation score:
D3Z3U5D3Z3U5_MOUSE
Activated CDC42 kinase 1
Tnk2
1,023Annotation score:
A0A0R4J1L0A0A0R4J1L0_MOUSE
Activated CDC42 kinase 1
Tnk2
1,008Annotation score:
D3Z3U7D3Z3U7_MOUSE
Activated CDC42 kinase 1
Tnk2 mCG_130126
550Annotation score:
E9QN61E9QN61_MOUSE
Activated CDC42 kinase 1
Tnk2
264Annotation score:
E9PWA3E9PWA3_MOUSE
Activated CDC42 kinase 1
Tnk2
98Annotation score:
E9QN60E9QN60_MOUSE
Activated CDC42 kinase 1
Tnk2
27Annotation score:
E9Q5M1E9Q5M1_MOUSE
Activated CDC42 kinase 1
Tnk2
165Annotation score:
A0A1Y7VJA6A0A1Y7VJA6_MOUSE
Activated CDC42 kinase 1
Tnk2
97Annotation score:
There is more potential isoformShow all

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_001334114.1, NM_001347185.1
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

Similar proteinsi

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_001334114.1, NM_001347185.1
NP_058068.2, NM_016788.3
UniGeneiMm.251115

3D structure databases

ProteinModelPortaliO54967
SMRiO54967
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi206174, 7 interactors
DIPiDIP-57223N
IntActiO54967, 3 interactors
MINTiO54967
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
PROiPR:O54967
SOURCEiSearch...

Gene expression databases

CleanExiMM_TNK2

Family and domain databases

Gene3Di4.10.680.10, 1 hit
InterProiView protein in InterPro
IPR030220 Ack1
IPR037085 Cdc42-bd-like_dom_sf
IPR015116 Cdc42_binding_dom-like
IPR011009 Kinase-like_dom_sf
IPR021619 Mig-6
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR036028 SH3-like_dom_sf
IPR001452 SH3_domain
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR009060 UBA-like_sf
PANTHERiPTHR14254:SF4 PTHR14254:SF4, 1 hit
PfamiView protein in Pfam
PF09027 GTPase_binding, 1 hit
PF11555 Inhibitor_Mig-6, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF14604 SH3_9, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00326 SH3, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF46934 SSF46934, 1 hit
SSF50044 SSF50044, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit
PS50002 SH3, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiACK1_MOUSE
AccessioniPrimary (citable) accession number: O54967
Secondary accession number(s): Q0Z844, Q8C2U0, Q8K0K4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 24, 2003
Last sequence update: December 4, 2007
Last modified: November 7, 2018
This is version 166 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

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