Global phosphoproteomics reveals crosstalk between Bcr-Abl and negative feedback mechanisms controlling Src signaling.
Global phosphoproteomics reveals crosstalk between Bcr-Abl and negative feedback mechanisms controlling Src signaling.
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DOI：
10.1126/scisignal.2001314
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发表时间：
2011-03-29
影响因子：
7.3
通讯作者：
Graeber TG
中科院分区：
文献类型：
--
作者：
Rubbi L;Titz B;Brown L;Galvan E;Komisopoulou E;Chen SS;Low T;Tahmasian M;Skaggs B;Müschen M;Pellegrini M;Graeber TG
In subtypes and late stages of leukemias driven by the tyrosine kinase fusion protein Bcr-Abl, Src signaling critically contributes to the leukemic phenotype. We performed global tyrosine phosphoprofiling using quantitative mass spectrometry of Bcr-Abl transformed cells in which the activities of the Src family kinases (SFKs) were perturbed to build a detailed context-dependent network of cancer signaling. Perturbation of the SFKs Lyn and Hck with genetics or inhibitors revealed Bcr-Abl downstream phosphorylation events either mediated by or independent of SFKs. We identified multiple negative feedback mechanisms within the network of signaling events affected by Bcr-Abl and SFKs, and found that Bcr-Abl attenuated these inhibitory mechanisms. The Csk binding protein Pag1 (also known as Cbp) and the tyrosine phosphatase Ptpn18 both mediated negative feedback to SFKs. We observed Bcr-Abl-mediated phosphorylation of the phosphatase Shp2 (Ptpn11) and this may contribute to the suppression of these negative feedback mechanisms to promote Bcr-Abl-activated SFK signaling. Csk and a kinase-deficient Csk mutant both produced similar globally repressive signaling consequences, suggesting a critical role for the adaptor protein function of Csk in its inhibition of Bcr-Abl and SFK signaling. The identified Bcr-Abl-activated SFK regulatory mechanisms are candidates for dysregulation during leukemia progression and acquisition of SFK-mediated drug resistance.
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影响因子：
4.8
作者：
Chong, YP;Mulhern, TD;Cheng, HC
通讯作者：
Cheng, HC
影响因子：
46.9
作者：
Dengjel, Joern;Akimov, Vyacheslav;Andersen, Jens S.
通讯作者：
Andersen, Jens S.
SH2-激酶结构域的结构耦合将FES和ABL底物识别和激酶激活联系起来。
影响因子：
64.5
作者：
Filippakopoulos, Panagis;Kofler, Michael;Hantschel, Oliver;Gish, Gerald D.;Grebien, Florian;Salah, Eidarus;Neudecker, Philipp;Kay, Lewis E.;Turk, Benjamin E.;Superti-Furga, Giulio;Pawson, Tony;Knapp, Stefan
通讯作者：
Knapp, Stefan
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1073/pnas.0504952102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Carter, TA;Wodicka, LM;Lockhart, DJ
通讯作者：
Lockhart, DJ