The activation mechanism of ACK1 (activated Cdc42-associated tyrosine kinase 1)

2012 ◽  
Vol 445 (2) ◽  
pp. 255-264 ◽  
Author(s):  
Qiong Lin ◽  
Jian Wang ◽  
Chandra Childress ◽  
Wannian Yang
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Molecular Mechanism ◽  
Growth Factor Receptor ◽  
Activation Mechanism ◽  
Src Homology 3 ◽  
Src Homology 3 Domain ◽  
Src Homology ◽  
Epidermal Growth

ACK [activated Cdc42 (cell division cycle 42)-associated tyrosine kinase; also called TNK2 (tyrosine kinase, non-receptor, 2)] is activated in response to multiple cellular signals, including cell adhesion, growth factor receptors and heterotrimeric G-protein-coupled receptor signalling. However, the molecular mechanism underlying activation of ACK remains largely unclear. In the present study, we demonstrated that interaction of the SH3 (Src homology 3) domain with the EBD [EGFR (epidermal growth factor receptor)-binding domain] in ACK1 forms an auto-inhibition of the kinase activity. Release of this auto-inhibition is a key step for activation of ACK1. Mutation of the SH3 domain caused activation of ACK1, independent of cell adhesion, suggesting that cell adhesion-mediated activation of ACK1 is through releasing the auto-inhibition. A region at the N-terminus of ACK1 (Leu10–Leu14) is essential for cell adhesion-mediated activation. In the activation of ACK1 by EGFR signalling, Grb2 (growth-factor-receptor-bound protein 2) mediates the interaction of ACK1 with EGFR through binding to the EBD and activates ACK1 by releasing the auto-inhibition. Furthermore, we found that mutation of Ser445 to proline caused constitutive activation of ACK1. Taken together, our studies have revealed a novel molecular mechanism underlying activation of ACK1.

scholarly journals Molecular Mechanism for a Role of SHP2 in Epidermal Growth Factor Receptor Signaling

2003 ◽  
Vol 23 (21) ◽  
pp. 7875-7886 ◽  
Author(s):  
Yehenew M. Agazie ◽  
Michael J. Hayman
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Plasma Membrane ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Molecular Mechanism ◽  
Receptor Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Tyrosine Kinase Signaling ◽  
Epidermal Growth

ABSTRACT The Src homology 2-containing phosphotyrosine phosphatase (SHP2) is primarily a positive effector of receptor tyrosine kinase signaling. However, the molecular mechanism by which SHP2 effects its biological function is unknown. In this report, we provide evidence that defines the molecular mechanism and site of action of SHP2 in the epidermal growth factor-induced mitogenic pathway. We demonstrate that SHP2 acts upstream of Ras and functions by increasing the half-life of activated Ras (GTP-Ras) in the cell by interfering with the process of Ras inactivation catalyzed by Ras GTPase-activating protein (RasGAP). It does so by inhibition of tyrosine phosphorylation-dependent translocation of RasGAP to the plasma membrane, to its substrate (GTP-Ras) microdomain. Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling, which may also serve as a model to describe its role in other receptor tyrosine kinase signaling pathways.

scholarly journals Src Homology 3-Domain Growth Factor Receptor-Bound 2-Like (Endophilin) Interacting Protein 1, a Novel Neuronal Protein that Regulates Energy Balance

Endocrinology ◽  
2005 ◽  
Vol 146 (9) ◽  
pp. 3757-3764 ◽  
Author(s):  
James Trevaskis ◽  
Ken Walder ◽  
Victoria Foletta ◽  
Lyndal Kerr-Bayles ◽  
Janine McMillan ◽  
...  
Keyword(s):  
Body Weight ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Domain Growth ◽  
Interacting Protein ◽  
Src Homology 3 ◽  
Src Homology 3 Domain ◽  
Src Homology ◽  
The Brain ◽  
Growth Factor Receptor Bound

Abstract To identify genes involved in the central regulation of energy balance, we compared hypothalamic mRNA from lean and obese Psammomys obesus, a polygenic model of obesity, using differential display PCR. One mRNA transcript was observed to be elevated in obese, and obese diabetic, P. obesus compared with lean animals and was subsequently found to be increased 4-fold in the hypothalamus of lethal yellow agouti (Ay/a) mice, a murine model of obesity and diabetes. Intracerebroventricular infusion of antisense oligonucleotide targeted to this transcript selectively suppressed its hypothalamic mRNA levels and resulted in loss of body weight in both P. obesus and Sprague Dawley rats. Reductions in body weight were mediated by profoundly reduced food intake without a concomitant reduction in metabolic rate. Yeast two-hybrid screening, and confirmation in mammalian cells by bioluminescence resonance energy transfer analysis, demonstrated that the protein it encodes interacts with endophilins, mediators of synaptic vesicle recycling and receptor endocytosis in the brain. We therefore named this transcript Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1). SGIP1 encodes a large proline-rich protein that is expressed predominantly in the brain and is highly conserved between species. Together these data suggest that SGIP1 is an important and novel member of the group of neuronal molecules required for the regulation of energy homeostasis.

scholarly journals The Small 11-kDa Protein from B19 Parvovirus Binds Growth Factor Receptor-Binding Protein 2 in Vitro in a Src Homology 3 Domain/Ligand-Dependent Manner

Virology ◽  
2001 ◽  
Vol 291 (2) ◽  
pp. 285-291 ◽  
Author(s):  
Mannie M.Y. Fan ◽  
Lillian Tamburic ◽  
Cynthia Shippam-Brett ◽  
Darren B. Zagrodney ◽  
Caroline R. Astell
Keyword(s):  
Growth Factor ◽  
Receptor Binding ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Src Homology 3 ◽  
B19 Parvovirus ◽  
Src Homology 3 Domain ◽  
Src Homology ◽  
Receptor Binding Protein

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Swathi R. Shetty ◽  
Ragini Yeeravalli ◽  
Tanya Bera ◽  
Amitava Das
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Type I ◽  
Egfr Inhibition ◽  
Epidermal Growth

: Epidermal growth factor receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that trigger tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Further, the mechanisms of action of potential molecules at various stages of drug development as well as clinically approved drugs for breast cancer treatment are illustrated.

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