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Regulation of ack-family nonreceptor tyrosine kinases.

Prieto-Echagüe V, Miller WT - J Signal Transduct (2011)

Bottom Line: Ack1 exerts some of its effects via protein-protein interactions that are independent of its kinase activity.Inappropriate Ack1 activation and signaling has been implicated in the development, progression, and metastasis of several forms of cancer.Thus, there is increasing interest in Ack1 as a drug target, and studies of the regulatory properties of the enzyme may reveal features that can be exploited in inhibitor design.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, School of Medicine, Stony Brook University, Basic Science Tower T5, Nicolls Road, Stony Brook, NY 11794, USA.

ABSTRACT
Ack family non-receptor tyrosine kinases are unique with regard to their domain composition and regulatory properties. Human Ack1 (activated Cdc42-associated kinase) is ubiquitously expressed and is activated by signals that include growth factors and integrin-mediated cell adhesion. Stimulation leads to Ack1 autophosphorylation and to phosphorylation of additional residues in the C-terminus. The N-terminal SAM domain is required for full activation. Ack1 exerts some of its effects via protein-protein interactions that are independent of its kinase activity. In the basal state, Ack1 activity is suppressed by an intramolecular interaction between the catalytic domain and the C-terminal region. Inappropriate Ack1 activation and signaling has been implicated in the development, progression, and metastasis of several forms of cancer. Thus, there is increasing interest in Ack1 as a drug target, and studies of the regulatory properties of the enzyme may reveal features that can be exploited in inhibitor design.

No MeSH data available.


Related in: MedlinePlus

Residues important for Ack1 function. Phosphorylation sites are indicated in black. Tyr284 is the major site of autophosphorylation    [38]. Tyr518, Tyr826, Tyr857, and Tyr858 were identified in proteomic studies    [51–54]. Cancer-associated mutations are in blue    [55]. Point mutations reported to affect Ack1 autophosphorylation are shown in green    [18, 56, 57]. The numbering scheme used corresponds to the accession number Q07912.
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fig2: Residues important for Ack1 function. Phosphorylation sites are indicated in black. Tyr284 is the major site of autophosphorylation [38]. Tyr518, Tyr826, Tyr857, and Tyr858 were identified in proteomic studies [51–54]. Cancer-associated mutations are in blue [55]. Point mutations reported to affect Ack1 autophosphorylation are shown in green [18, 56, 57]. The numbering scheme used corresponds to the accession number Q07912.

Mentions: A major autophosphorylation site has been mapped to the Y284 in the activation loop [38]. A construct containing residues 1- 476, corresponding to the N-terminus, the kinase domain, the SH3 domain, and the CRIB domain (Nt-Kinase-SH3-CRIB) is the longest construct that has been purified to homogeneity [38]. This construct is activated, although modestly (3-fold), by the phosphorylation of Y284. Proteomic approaches have identified other phosphorylation sites in Ack1. In BCR-ABL transformed cell lines, Y826, Y856, and Y857 of Ack1 are phosphorylated [51] (Figure 2). The phosphorylation of Y826 was also identified in a study of phosphorylated proteins downstream of insulin signaling [52]. Y857 of Ack1 was identified in a mass spectrometry study in which protein phosphorylation events downstream of the EGFR-family member HER2 were analyzed [53]. In addition, the phosphorylation of Y518 was identified in a study of global tyrosine phosphorylation patterns in cancer cells [54]. The biological significance of these phosphorylation sites remains to be determined. Interestingly, Y826, Y857, and Y858 are located in the Mig6-homology region (MHR), a portion of Ack1 that participates in inhibitory intramolecular interactions [58]. It is possible that the MHR of Ack1 is a substrate for oncogenic BCR-ABL, or for insulin and EGF receptors, resulting the release of autoinhibition.


Regulation of ack-family nonreceptor tyrosine kinases.

Prieto-Echagüe V, Miller WT - J Signal Transduct (2011)

Residues important for Ack1 function. Phosphorylation sites are indicated in black. Tyr284 is the major site of autophosphorylation    [38]. Tyr518, Tyr826, Tyr857, and Tyr858 were identified in proteomic studies    [51–54]. Cancer-associated mutations are in blue    [55]. Point mutations reported to affect Ack1 autophosphorylation are shown in green    [18, 56, 57]. The numbering scheme used corresponds to the accession number Q07912.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3101793&req=5

fig2: Residues important for Ack1 function. Phosphorylation sites are indicated in black. Tyr284 is the major site of autophosphorylation [38]. Tyr518, Tyr826, Tyr857, and Tyr858 were identified in proteomic studies [51–54]. Cancer-associated mutations are in blue [55]. Point mutations reported to affect Ack1 autophosphorylation are shown in green [18, 56, 57]. The numbering scheme used corresponds to the accession number Q07912.
Mentions: A major autophosphorylation site has been mapped to the Y284 in the activation loop [38]. A construct containing residues 1- 476, corresponding to the N-terminus, the kinase domain, the SH3 domain, and the CRIB domain (Nt-Kinase-SH3-CRIB) is the longest construct that has been purified to homogeneity [38]. This construct is activated, although modestly (3-fold), by the phosphorylation of Y284. Proteomic approaches have identified other phosphorylation sites in Ack1. In BCR-ABL transformed cell lines, Y826, Y856, and Y857 of Ack1 are phosphorylated [51] (Figure 2). The phosphorylation of Y826 was also identified in a study of phosphorylated proteins downstream of insulin signaling [52]. Y857 of Ack1 was identified in a mass spectrometry study in which protein phosphorylation events downstream of the EGFR-family member HER2 were analyzed [53]. In addition, the phosphorylation of Y518 was identified in a study of global tyrosine phosphorylation patterns in cancer cells [54]. The biological significance of these phosphorylation sites remains to be determined. Interestingly, Y826, Y857, and Y858 are located in the Mig6-homology region (MHR), a portion of Ack1 that participates in inhibitory intramolecular interactions [58]. It is possible that the MHR of Ack1 is a substrate for oncogenic BCR-ABL, or for insulin and EGF receptors, resulting the release of autoinhibition.

Bottom Line: Ack1 exerts some of its effects via protein-protein interactions that are independent of its kinase activity.Inappropriate Ack1 activation and signaling has been implicated in the development, progression, and metastasis of several forms of cancer.Thus, there is increasing interest in Ack1 as a drug target, and studies of the regulatory properties of the enzyme may reveal features that can be exploited in inhibitor design.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, School of Medicine, Stony Brook University, Basic Science Tower T5, Nicolls Road, Stony Brook, NY 11794, USA.

ABSTRACT
Ack family non-receptor tyrosine kinases are unique with regard to their domain composition and regulatory properties. Human Ack1 (activated Cdc42-associated kinase) is ubiquitously expressed and is activated by signals that include growth factors and integrin-mediated cell adhesion. Stimulation leads to Ack1 autophosphorylation and to phosphorylation of additional residues in the C-terminus. The N-terminal SAM domain is required for full activation. Ack1 exerts some of its effects via protein-protein interactions that are independent of its kinase activity. In the basal state, Ack1 activity is suppressed by an intramolecular interaction between the catalytic domain and the C-terminal region. Inappropriate Ack1 activation and signaling has been implicated in the development, progression, and metastasis of several forms of cancer. Thus, there is increasing interest in Ack1 as a drug target, and studies of the regulatory properties of the enzyme may reveal features that can be exploited in inhibitor design.

No MeSH data available.


Related in: MedlinePlus