Q5U2X5 (ACK1_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Activated CDC42 kinase 1
Short name=ACK-1
EC=2.7.10.2
EC=2.7.11.1

Alternative name(s):
Tyrosine kinase non-receptor protein 2

Gene names

Name:	Tnk2
Synonyms:	Ack1

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	1040 AA.
Sequence status	Complete.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	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 By similarity.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. UniProtKB Q07912 ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium By similarity. UniProtKB Q07912
Subunit structure	Homodimer. Interacts with CDC42. 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). Interacts with EGFR, and this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts (via kinase domain) with AKT1. 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. Interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote association with NEDD4 By similarity.
Subcellular location	Cell membrane By similarity. Nucleus By similarity. Endosome By similarity. Cell junction › adherens junction By similarity. Cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side By similarity. Cytoplasmic vesicle › clathrin-coated vesicle By similarity. Membrane › clathrin-coated pit By similarity. Note: The Tyr-284 phosphorylated form is found both in the membrane and nucleus. Co-localizes with EGFR on endosomes. Nuclear translocation is CDC42-dependent By similarity. UniProtKB O54967
Domain	The EBD (EGFR-binding domain) domain is necessary for interaction with EGFR By similarity. The SAM-like domain is necessary for NEDD4-mediated ubiquitination. Promotes membrane localization and dimerization to allow for autophosphorylation By similarity. The UBA domain binds both poly- and mono-ubiquitin By similarity.
Post-translational modification	Autophosphorylation regulates kinase activity. Phosphorylation on Tyr-518 is required for interaction with SRC and is observed during association with clathrin-coated pits By similarity. Polyubiquitinated by NEDD4 and NEDD4L. Degradation can be induced by EGF and is lysosome-dependent By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. UniProtKB Q07912 Contains 1 protein kinase domain. Contains 1 SH3 domain. Contains 1 UBA domain.

Ontologies

Keywords
Biological process	Endocytosis
Cellular component	Cell junction Cell membrane Coated pit Cytoplasmic vesicle Endosome Membrane Nucleus
Domain	SH3 domain
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase Tyrosine-protein kinase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	endocytosis Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	adherens junction Inferred from electronic annotation. Source: UniProtKB-SubCell clathrin-coated vesicle Inferred from electronic annotation. Source: UniProtKB-SubCell coated pit Inferred from electronic annotation. Source: UniProtKB-SubCell cytoplasmic vesicle membrane Inferred from electronic annotation. Source: UniProtKB-SubCell endosome Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW non-membrane spanning protein tyrosine kinase activity Inferred from electronic annotation. Source: EC protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW protein tyrosine kinase activity Inferred from direct assay PubMed 16052498. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1040	1040	Activated CDC42 kinase 1		PRO_0000312830
Regions
	Domain	126 – 385	260	Protein kinase
	Domain	373 – 448	76	SH3
	Domain	958 – 998	41	UBA
	Nucleotide binding	132 – 140	9	ATP By similarity UniProtKB P00517
	Region	1 – 110	110	SAM-like domain By similarity
	Region	623 – 652	30	Required for interaction with SRC By similarity
	Region	632 – 635	4	Required for interaction with NEDD4 By similarity
	Region	733 – 876	144	EBD domain By similarity
	Compositional bias	577 – 935	359	Pro-rich
Sites
	Active site	252	1	Proton acceptor By similarity UniProtKB P00517
	Binding site	158	1	ATP By similarity UniProtKB O54967
Amino acid modifications
	Modified residue	284	1	Phosphotyrosine; by SRC and autocatalysis By similarity UniProtKB Q07912
	Modified residue	518	1	Phosphotyrosine By similarity UniProtKB Q07912
	Modified residue	827	1	Phosphotyrosine By similarity UniProtKB Q07912
	Modified residue	859	1	Phosphotyrosine By similarity UniProtKB Q07912
	Modified residue	872	1	Phosphotyrosine By similarity
	Modified residue	881	1	Phosphoserine By similarity

Sequences

	Sequence		Length	Mass (Da)
	Q5U2X5 [UniParc]. Last modified December 7, 2004. Version 1. Checksum: 0624944919F821F6	FASTA	1,040	115,068
	10 20 30 40 50 60 MQPEEGTGWL LELLSEVQLQ QYFLRLRDDL NITRLSHFEY VKNEDLEKIG MGRPGQRRLW 70 80 90 100 110 120 EAVKRRKAMC KRKSWMSKVF SGKRQEAEFP SHHSQSTFRK PSPTPGGLAG EGTLQSLTCL 130 140 150 160 170 180 IGEKDLRLLE KLGDGSFGVV RRGEWDAPAG KTVSVAVKCL KPDVLSQPEA MDDFIREVNA 190 200 210 220 230 240 MHSLDHRNLI RLYGVVLTPP MKMVTELAPL GSLLDRLRKH QGHFLLGTLS RYAVQVAEGM 250 260 270 280 290 300 GYLESKRFIH RDLAARNLLL ATRDLVKIGD FGLMRALPQN DGHYVMQEHR KVPFAWCAPE 310 320 330 340 350 360 SLKTRTFSHA SDTWMFGVTL WEMFTYGQEP WIGLNGSQIL HKIDKEGERL PRPEDCPQDI 370 380 390 400 410 420 YNVMVQCWAH KPEDRPTFVA LRDFLLEAQP TDMRALQDFE EPDKLHIQMN DVITVIEGRA 430 440 450 460 470 480 ENYWWRGQNT RTLCVGPFPR NVVTSVAGLS AQDISQPLQN SFIHTGHGDS DPRHCWGFPD 490 500 510 520 530 540 RIDELYLGNP MDPPDLLSVE LSTSRPTQHL GRMKKPTYDP VSEDPDPLSS DFKRLGLRKP 550 560 570 580 590 600 ALPRGLWLAK PSARVPGTKA GRSSGGEVTL IDFGEEPVAP TPRPCAPSLA QLAMDACSLL 610 620 630 640 650 660 DKTPPQSPTR ALPRPLHPTP VVDWDARPLP PPPAYDDVAQ DEDDFEVCSI NSTLVSAGLP 670 680 690 700 710 720 TGPSQGETNY AFVPEQAQLP PALEDNLFLP PQGGGQPPSS AQTAEIFQAL QQECMRQLQV 730 740 750 760 770 780 PTGQLTPSPT PGGDDKPQVP PRVPIPPRPT RPRVGLSPAP LGEEEASRWP GPSSPPRVPP 790 800 810 820 830 840 REPLSPQGSR TPSPLVPPGS SPLPHRLSSS PGKTMPTTQS FASDPKYATP QVIQAPGPRA 850 860 870 880 890 900 GPCILPIVRD GRKVSSTHYY LLPERPPYLE RYQRFLREAQ SPEEPAALPV PPLLPPPSTP 910 920 930 940 950 960 APAAPTATVR PMPQAAPDPK ANFSTNNSNP GAQPPSLRAS ARLPQRGCPG DGQEAARPAD 970 980 990 1000 1010 1020 KVQMLQAMVH GVTTEECQAA LRSHSWSIQR AAQYLKVEQL FGLGLRPRVE CHKVLEMFDW 1030 1040 NLEQAGCHLL GSCGPAHHKR

References

[1]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney.

Cross-references

Sequence databases
EMBL GenBank DDBJ	BC085825 mRNA. Translation: AAH85825.1.
IPI	IPI00362119.
RefSeq	NP_001008337.1. NM_001008336.1.
UniGene	Rn.98335.
3D structure databases
HSSP	HSSP built from PDB template 1U54 based on UniProtKB Q07912.
ProteinModelPortal	Q5U2X5.
SMR	Q5U2X5. Positions 117-388, 447-489.
ModBase	Search...
Protein-protein interaction databases
STRING	10116.ENSRNOP00000040625.
PTM databases
PhosphoSite	Q5U2X5.
Proteomic databases
PaxDb	Q5U2X5.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	303882.
KEGG	rno:303882.
Organism-specific databases
CTD	10188.
RGD	1346409. Tnk2.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000168225.
HOVERGEN	HBG100429.
KO	K08886.
Gene expression databases
ArrayExpress	Q5U2X5.
Genevestigator	Q5U2X5.
Family and domain databases
Gene3D	4.10.680.10. 1 hit.
InterPro	IPR015116. Cdc42_binding_dom_like. IPR021619. Inhibitor_Mig-6. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_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. IPR000449. UBA/transl_elong_EF1B_N. [Graphical view]
Pfam	PF09027. GTPase_binding. 1 hit. PF11555. Inhibitor_Mig-6. 1 hit. PF07714. Pkinase_Tyr. 1 hit. PF00627. UBA. 1 hit. [Graphical view]
PRINTS	PR00109. TYRKINASE.
SMART	SM00326. SH3. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit. SSF50044. SH3. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. PS50002. SH3. 1 hit. PS50030. UBA. False negative. [Graphical view]
ProtoNet	Search...
Other
NextBio	652234.

Entry information

Entry name

ACK1_RAT

Accession

Primary (citable) accession number: Q5U2X5

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 4, 2007
Last sequence update:	December 7, 2004
Last modified:	May 1, 2013
This is version 70 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program