DB code: M00335

RLCP classification 3.103.130000.1162 : Transfer
CATH domain 1.10.150.- : DNA polymerase; domain 1
3.30.200.20 : Phosphorylase Kinase; domain 1
1.10.510.10 : Transferase(Phosphotransferase); domain 1 Catalytic domain
2.30.30.40 : SH3 type barrels.
4.10.680.10 : Activated P21cdc42hs Kinase; Chain B
-.-.-.- :
-.-.-.- :
1.10.8.- : Helicase, Ruva Protein; domain 3
E.C. 2.7.10.2 2.7.11.1
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
1.10.510.10 : Transferase(Phosphotransferase); domain 1 M00125 M00124 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00326 M00327 M00328 M00329 M00330 M00331 M00332 M00333 M00339 M00344
2.30.30.40 : SH3 type barrels. M00183 M00043 M00130 T00256 M00304
3.30.200.20 : Phosphorylase Kinase; domain 1 M00125 M00124 M00131 T00224 M00127 M00129 M00130 M00132 M00136 M00196 M00197 M00198 M00304 M00323 M00325 M00326 M00327 M00328 M00329 M00330 M00331 M00332 M00333 M00339 M00344 D00298

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
Q07912 Activated CDC42 kinase 1
ACK-1
EC 2.7.10.2
EC 2.7.11.1
Tyrosine kinase non-receptor protein 2
NP_001010938.1 (Protein)
NM_001010938.1 (DNA/RNA sequence)
NP_005772.3 (Protein)
NM_005781.4 (DNA/RNA sequence)
PF09027 (GTPase_binding)
PF11555 (Inhibitor_Mig-6)
PF07714 (Pkinase_Tyr)
[Graphical View]

KEGG enzyme name
Non-specific protein-tyrosine kinase
(EC 2.7.10.2 )
ACK1
(EC 2.7.10.2 )
ACK2
(EC 2.7.10.2 )
Cytoplasmic protein tyrosine kinase
(EC 2.7.10.2 )
Protein-tyrosine kinase (ambiguous)
(EC 2.7.10.2 )
TNK1
(EC 2.7.10.2 )
Non-specific serine/threonine protein kinase
(EC 2.7.11.1 )
protein kinase (phosphorylating)
(EC 2.7.11.1 )
protein phosphokinase
(EC 2.7.11.1 )
protein serine kinase
(EC 2.7.11.1 )
protein serine-threonine kinase
(EC 2.7.11.1 )
protein-serine kinase
(EC 2.7.11.1 )
serine kinase
(EC 2.7.11.1 )
serine protein kinase
(EC 2.7.11.1 )
serine(threonine) protein kinase
(EC 2.7.11.1 )
serine/threonine protein kinase
(EC 2.7.11.1 )

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
Q07912 ACK1_HUMAN ATP + a protein = ADP + a phosphoprotein. ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Interacts with NEDD4 (via WW3 domain). NEDD4L and EGF promote association with NEDD4 (By similarity). Homodimer. Interacts with AR, CDC42, WWASL and WWOX. 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. Cell membrane. Nucleus. Endosome. Cell junction, adherens junction (By similarity). Cytoplasmic vesicle membrane, Peripheral membrane protein, Cytoplasmic side. Cytoplasmic vesicle, clathrin-coated vesicle. Membrane, clathrin-coated pit. 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. Magnesium.

KEGG Pathways
Map code Pathways E.C.

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00305 C00002 C00585 C00017 C00008 C01167 C00562
E.C. 2.7.10.2
2.7.11.1
2.7.10.2
2.7.11.1
2.7.10.2
2.7.11.1
2.7.10.2
2.7.11.1
2.7.10.2
2.7.11.1
Compound Mg ATP [protein]-L-tyrosine Protein ADP [protein]-L-tyrosine phosphate Phosphoprotein
Type divalent metal (Ca2+, Mg2+) amine group,nucleotide aromatic ring (only carbon atom),peptide/protein peptide/protein amine group,nucleotide aromatic ring (only carbon atom),peptide/protein,phosphate group/phosphate ion peptide/protein,phosphate group/phosphate ion
ChEBI 18420
15422
16761
PubChem 888
5957
6022
1u46A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1u46B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1u4dA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1u4dB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1u54A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Analogue:ACP Unbound Unbound Unbound Unbound Unbound
1u54B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Analogue:ACP Unbound Unbound Unbound Unbound Unbound
3eqpA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3eqpB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3eqrA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3eqrB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
4ewhA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
4ewhB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1u46A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1u46B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1u4dA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1u4dB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1u54A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:2x_MG Unbound Unbound Unbound Unbound Unbound Unbound
1u54B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Bound:2x_MG Unbound Unbound Unbound Unbound Unbound Unbound
3eqpA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3eqpB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3eqrA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3eqrB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
4ewhA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
4ewhB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1cf4B Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Literature [3] & Swiss-prot;Q07912

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1u46A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 134-137, 160-167
1u46B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 134-137, 160-170
1u4dA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 160-170
1u4dB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 161-169
1u54A01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 135-137, 161-169
1u54B01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 135-137, 161-168
3eqpA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 161-166
3eqpB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 161-166
3eqrA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain invisible 162-167
3eqrB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
4ewhA01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
4ewhB01 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain
1u46A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) TYR 284 (Auto-Phospholyration) invisible 280, 287-291
1u46B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) TYR 284 (Auto-Phospholyration) invisible 223-224
1u4dA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) TYR 284 (Auto-Phospholyration) invisible 280-281, 287-291
1u4dB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) TYR 284 (Auto-Phospholyration) invisible 222-224
1u54A02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) PTR 284 (Auto-Phospholyration) invisible 291
1u54B02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) TYR 284 (Auto-Phospholyration)
3eqpA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) TYR 284 (Auto-Phospholyration)
3eqpB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) TYR 284 (Auto-Phospholyration)
3eqrA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) TYR 284 (Auto-Phospholyration)
3eqrB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) TYR 284 (Auto-Phospholyration)
4ewhA02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) PTR 284 (Auto-Phospholyration)
4ewhB02 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain ASP 252;ARG 256 ASN 257;ASP 270 (Magnesium binding) PTR 284 (Auto-Phospholyration)
1cf4B Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain

References for Catalytic Mechanism
References Sections No. of steps in catalysis

References
[1]
Resource
Comments
Medline ID
PubMed ID 10360579
Journal Nature
Year 1999
Volume 399
Pages 384-8
Authors Mott HR, Owen D, Nietlispach D, Lowe PN, Manser E, Lim L, Laue ED
Title Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK.
Related PDB 1cf4
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 14506255
Journal J Biol Chem
Year 2003
Volume 278
Pages 47713-23
Authors Yokoyama N, Miller WT
Title Biochemical properties of the Cdc42-associated tyrosine kinase ACK1. Substrate specificity, authphosphorylation, and interaction with Hck.
Related PDB
Related UniProtKB
[3]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 107-395, PHOSPHORYLATION AT TYR-284.
Medline ID
PubMed ID 15308621
Journal J Biol Chem
Year 2004
Volume 279
Pages 44039-45
Authors Lougheed JC, Chen RH, Mak P, Stout TJ
Title Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1.
Related PDB 1u46 1u4d 1u54
Related UniProtKB Q07912
[4]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 117-392 IN COMPLEX WITH INHIBITOR, CATALYTIC ACTIVITY.
Medline ID
PubMed ID 18993068
Journal Bioorg Med Chem Lett
Year 2008
Volume 18
Pages 6352-6
Authors Kopecky DJ, Hao X, Chen Y, Fu J, Jiao X, Jaen JC, Cardozo MG, Liu J, Wang Z, Walker NP, Wesche H, Li S, Farrelly E, Xiao SH, Kayser F
Title Identification and optimization of N3,N6-diaryl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamines as a novel class of ACK1 inhibitors.
Related PDB 3eqp 3eqr
Related UniProtKB Q07912
[5]
Resource
Comments SUBUNIT, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-284, DOMAIN SAM-LIKE.
Medline ID
PubMed ID 20979614
Journal BMC Biochem
Year 2010
Volume 11
Pages 42
Authors Prieto-Echague V, Gucwa A, Brown DA, Miller WT
Title Regulation of Ack1 localization and activity by the amino-terminal SAM domain.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 20110370
Journal J Biol Chem
Year 2010
Volume 285
Pages 10605-15
Authors Prieto-Echague V, Gucwa A, Craddock BP, Brown DA, Miller WT
Title Cancer-associated mutations activate the nonreceptor tyrosine kinase Ack1.
Related PDB
Related UniProtKB
[7]
Resource
Comments PHOSPHORYLATION AT TYR-284, INTERACTION WITH SRC.
Medline ID
PubMed ID 21309750
Journal Biochem J
Year 2011
Volume 435
Pages 355-64
Authors Chan W, Sit ST, Manser E
Title The Cdc42-associated kinase ACK1 is not autoinhibited but requires Src for activation.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 21637378
Journal J Signal Transduct
Year 2011
Volume 2011
Pages 742372
Authors Prieto-Echague V, Miller WT
Title Regulation of ack-family nonreceptor tyrosine kinases.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 22929232
Journal Bioorg Med Chem Lett
Year 2012
Volume 22
Pages 6212-7
Authors Jiao X, Kopecky DJ, Liu J, Liu J, Jaen JC, Cardozo MG, Sharma R, Walker N, Wesche H, Li S, Farrelly E, Xiao SH, Wang Z, Kayser F
Title Synthesis and optimization of substituted furo[2,3-d]-pyrimidin-4-amines and 7H-pyrrolo[2,3-d]pyrimidin-4-amines as ACK1 inhibitors.
Related PDB 4ewh
Related UniProtKB

Comments
This enzyme belongs to Ack (activated Cdc42-associated kinase) nonreceptor tyrosine kinase family (see [8]). This enzyme is composed of N-terminal sterile alpha motif (SAM) domain, kinase domain, SH3 domain, Cdc42/Rac-interactive domain (CRIB), Clathrin binding motif, region that shares a high homology with Mitogen induced gene6 (Mig6), and C-terminal ubiquitin associated (UBA) domain.
The catalytic domain of this enzyme is homologous to that of proto-oncogene tyrosine-protein kinase ABL1 (M00130 in EzCatDB).

Created Updated
2011-12-28 2012-12-13