Activation of extracellular signal-regulated kinase but not of p38 mitogen-activated protein kinase pathways in lymphocytes requires allosteric activation of SOS

Jesse E. Jun, Ming Yang, Hang Chen, Arup K. Chakraborty, Jeroen P. Roose

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Thymocytes convert graded T cell receptor (TCR) signals into positive selection or deletion, and activation of extracellular signal- related kinase (ERK), p38, and Jun N-terminal protein kinase (JNK) mitogen-activated protein kinases (MAPKs) has been postulated to play a discriminatory role. Two families of Ras guanine nucleotide exchange factors (RasGEFs), SOS and RasGRP, activate Ras and the downstream RAF-MEK-ERK pathway. The pathways leading to lymphocyte p38 and JNK activation are less well defined. We previously described how RasGRP alone induces analog Ras-ERK activation while SOS and RasGRP cooperate to establish bimodal ERK activation. Here we employed computational modeling and biochemical experiments with model cell lines and thymocytes to show that TCR-induced ERK activation grows exponentially in thymocytes and that a W729E allosteric pocket mutant, SOS1, can only reconstitute analog ERK signaling. In agreement with RasGRP allosterically priming SOS, exponential ERK activation is severely decreased by pharmacological or genetic perturbation of the phospholipase Cγ (PLCγ)-diacylglycerol- RasGRP1 pathway. In contrast, p38 activation is not sharply thresholded and requires high-level TCR signal input. Rac and p38 activation depends on SOS1 expression but not allosteric activation. Based on computational predictions and experiments exploring whether SOS functions as a RacGEF or adaptor in Rac-p38 activation, we established that the presence of SOS1, but not its enzymatic activity, is critical for p38 activation.

Original languageEnglish
Pages (from-to)2470-2484
Number of pages15
JournalMolecular and Cellular Biology
Volume33
Issue number12
DOIs
StatePublished - Jun 2013
Externally publishedYes

Funding

FundersFunder number
National Cancer InstituteU54CA143874
National Institute of Allergy and Infectious DiseasesP01AI091580

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