In Situ Kinase Profiling Reveals Functionally Relevant Properties of Native Kinases

被引：276

作者：

Patricelli, Matthew P. ^{[1
]}

Nomanbhoy, Tyzoon K. ^{[1
]}

Wu, Jiangyue ^{[1
]}

Brown, Heidi ^{[1
]}

Zhou, David ^{[1
]}

Zhang, Jianming ^{[2
,3
]}

Jagannathan, Subadhra ^{[1
]}

Aban, Arwin ^{[1
]}

Okerberg, Eric ^{[1
]}

Herring, Chris ^{[1
]}

Nordin, Brian ^{[1
]}

Weissig, Helge ^{[1
]}

Yang, Qingkai ^{[4
]}

Lee, Jiing-Dwan ^{[4
]}

Gray, Nathanael S. ^{[2
,3
]}

Kozarich, John W. ^{[1
]}

机构：

[1] ActivX Biosci, La Jolla, CA 92037 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[4] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA

来源：

CHEMISTRY & BIOLOGY | 2011年 / 18卷 / 06期

关键词：

GROWTH-FACTOR RECEPTOR; P38 MAP KINASE; B-RAF KINASE; TYROSINE KINASE; PROTEOMICS STRATEGY; TUMOR PROGRESSION; PROTEIN-KINASES; INHIBITORS; POTENT; BRAF;

D O I：

10.1016/j.chembiol.2011.04.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Protein kinases are intensely studied mediators of cellular signaling, yet important questions remain regarding their regulation and in vivo properties. Here, we use a probe-based chemoprotemics platform to profile several well studied kinase inhibitors against >200 kinases in native cell proteomes and reveal biological targets for some of these inhibitors. Several striking differences were identified between native and recombinant kinase inhibitory profiles, in particular, for the Raf kinases. The native kinase binding profiles presented here closely mirror the cellular activity of these inhibitors, even when the inhibition profiles differ dramatically from recombinant assay results. Additionally, Raf activation events could be detected on live cell treatment with inhibitors. These studies highlight the complexities of protein kinase behavior in the cellular context and demonstrate that profiling with only recombinant/purified enzymes can be misleading.

引用

页码：699 / 710

页数：12

共 44 条

[1] Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors [J].