scholarly journals Flexibility and charge asymmetry in the activation loop of Src tyrosine kinases

2009 ◽  
Vol 74 (2) ◽  
pp. 378-389 ◽  
Author(s):  
Nilesh K. Banavali ◽  
Benoît Roux
Keyword(s):  
Tyrosine Kinases ◽  
Charge Asymmetry ◽  
Activation Loop ◽  
Src Tyrosine Kinases

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

2018 ◽  
Vol 11 (553) ◽  
pp. eaat5916 ◽  
Author(s):  
Kexin Shen ◽  
Jamie A. Moroco ◽  
Ravi K. Patel ◽  
Haibin Shi ◽  
John R. Engen ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Colony Formation ◽  
Family Members ◽  
Cellular Transformation ◽  
Soft Agar ◽  
Kinase Domain ◽  
Sh2 Domain ◽  
Mass Spectrometry Data ◽  
Activation Loop ◽  
Exchange Mass Spectrometry

Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, we investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.

Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

2018 ◽  
Vol 191 ◽  
pp. 123-134 ◽  
Author(s):  
Lillian R. Klug ◽  
Jason D. Kent ◽  
Michael C. Heinrich
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Activation Loop ◽  
Class Iii ◽  
Clinical Consequences

scholarly journals ErbB Receptor-induced Activation of Stat Transcription Factors Is Mediated by Src Tyrosine Kinases

1999 ◽  
Vol 274 (24) ◽  
pp. 17209-17218 ◽  
Author(s):  
Monilola A. Olayioye ◽  
Iwan Beuvink ◽  
Kay Horsch ◽  
John M. Daly ◽  
Nancy E. Hynes
Keyword(s):  
Transcription Factors ◽  
Tyrosine Kinases ◽  
Erbb Receptor ◽  
Src Tyrosine Kinases

scholarly journals Two Distinct Phosphorylation Pathways Have Additive Effects on Abl Family Kinase Activation

2003 ◽  
Vol 23 (11) ◽  
pp. 3884-3896 ◽  
Author(s):  
Keith Q. Tanis ◽  
Darren Veach ◽  
Henry S. Duewel ◽  
William G. Bornmann ◽  
Anthony J. Koleske
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Intramolecular Interactions ◽  
Activation Loop ◽  
Additive Effects ◽  
Nonreceptor Tyrosine Kinase ◽  
Kinase Activation ◽  
Surface Receptors ◽  
Nonreceptor Tyrosine Kinases ◽  
Stimulation Of

ABSTRACT The activities of the related Abl and Arg nonreceptor tyrosine kinases are kept under tight control in cells, but exposure to several different stimuli results in a two- to fivefold stimulation of kinase activity. Following the breakdown of inhibitory intramolecular interactions, Abl activation requires phosphorylation on several tyrosine residues, including a tyrosine in its activation loop. These activating phosphorylations have been proposed to occur either through autophosphorylation by Abl in trans or through phosphorylation of Abl by the Src nonreceptor tyrosine kinase. We show here that these two pathways mediate phosphorylation at distinct sites in Abl and Arg and have additive effects on Abl and Arg kinase activation. Abl and Arg autophosphorylate at several sites outside the activation loop, leading to 5.2- and 6.2-fold increases in kinase activity, respectively. We also find that the Src family kinase Hck phosphorylates the Abl and Arg activation loops, leading to an additional twofold stimulation of kinase activity. The autoactivation pathway may allow Abl family kinases to integrate or amplify cues relayed by Src family kinases from cell surface receptors.

Position of Src tyrosine kinases in the interaction between angiotensin II and endothelin in in vivo vascular protein synthesis

2005 ◽  
Vol 23 (2) ◽  
pp. 329-335 ◽  
Author(s):  
Pierre Beaucage ◽  
Marc Iglarz ◽  
Marc Servant ◽  
Rhian M Touyz ◽  
Pierre Moreau
Keyword(s):  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Tyrosine Kinases ◽  
Src Tyrosine Kinases

Src tyrosine kinases contribute to serotonin-mediated contraction by regulating calcium-dependent pathways in rat skeletal muscle arteries

2017 ◽  
Vol 469 (5-6) ◽  
pp. 767-777 ◽  
Author(s):  
Olga Zavaritskaya ◽  
Lubomir T. Lubomirov ◽  
Serdar Altay ◽  
Rudolf Schubert
Keyword(s):  
Skeletal Muscle ◽  
Tyrosine Kinases ◽  
Rat Skeletal Muscle ◽  
Calcium Dependent ◽  
Src Tyrosine Kinases

Linear and cyclic synthetic peptides related to the main autophosphorylation site of the Src tyrosine kinases as substrates and inhibitors of Lyn †

2009 ◽  
Vol 45 (6) ◽  
pp. 529-539 ◽  
Author(s):  
PAOLO RUZZA ◽  
ANDREA CALDERAN ◽  
BRUNO FILIPPI ◽  
BARBARA BIONDI ◽  
ARIANNA DONELLA DEANA ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Synthetic Peptides ◽  
Src Tyrosine Kinases ◽  
Autophosphorylation Site
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