Activation of the nonreceptor protein tyrosine kinase Ack by multiple extracellular stimuli
- 27 June 2006
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 103 (26) , 9796-9801
- https://doi.org/10.1073/pnas.0603714103
Abstract
Ack/Ack1 is a nonreceptor protein tyrosine kinase that comprises a tyrosine kinase core, an SH3 domain, a Cdc42-binding region, a Ralt homology region, and a proline-rich region. Here we describe a detailed characterization of the Ack protein as well as the chromosomal localization of human Ack (chromosome 3q29) and the primary structure of murine Ack. We demonstrate that Ack is ubiquitously expressed, with highest expression seen in thymus, spleen, and brain. Activation of integrins by cell adhesion on fibronectin leads to strong tyrosine phosphorylation and activation of Ack. Upon cell stimulation with EGF or PDGF, Ack is tyrosine-phosphorylated and recruited to activated EGF or PDGF receptors, respectively. A pool of endogenous Ack molecules is constitutively tyrosine-phosphorylated, even in starved cells. Moreover, tyrosine-phosphorylated Ack forms a stable complex with the adapter protein Nck via its SH2 domain. Finally, we have characterized a membrane-targeting sterile alpha motif-like domain in the amino terminus of Ack. Using several Ack mutants, we show that the amino-terminal and CRIB domains are necessary for Ack autophosphorylation, whereas the SH3 domain appears to have an autoinhibitory role. These experiments suggest a functional role for Ack as an early transducer of multiple extracellular stimuli.Keywords
This publication has 38 references indexed in Scilit:
- SNX9 as an adaptor for linking synaptojanin‐1 to the Cdc42 effector ACK1FEBS Letters, 2005
- The Cdc42 Target ACK2 Interacts with Sorting Nexin 9 (SH3PX1) to Regulate Epidermal Growth Factor Receptor DegradationJournal of Biological Chemistry, 2002
- Drosophila Ack Targets Its Substrate, the Sorting Nexin DSH3PX1, to a Protein Complex Involved in Axonal GuidanceJournal of Biological Chemistry, 2002
- Initial sequencing and analysis of the human genomeNature, 2001
- ARK-1 Inhibits EGFR Signaling in C. elegansMolecular Cell, 2000
- An intramolecular SH3-domain interaction regulates c-Abl activityNature Genetics, 1998
- Crystal structure of the Src family tyrosine kinase HckNature, 1997
- Three-dimensional structure of the tyrosine kinase c-SrcNature, 1997
- Regulatory intramolecular association in a tyrosine kinase of the Tec familyNature, 1997
- Translocation (2;3) in hematologic malignanciesCancer Genetics and Cytogenetics, 1986