Abstract:
:Chimeric antigen receptors (CARs) have recently been approved for the treatment of hematological malignancies, but our lack of understanding of the basic mechanisms that activate these proteins has made it difficult to optimize and control CAR-based therapies. In this study, we use phosphoproteomic mass spectrometry and mechanistic computational modeling to quantify the in vitro kinetics of individual tyrosine phosphorylation on a variety of CARs. We show that each of the 10 tyrosine sites on the CD28-CD3ζ CAR is phosphorylated by lymphocyte-specific protein-tyrosine kinase (LCK) with distinct kinetics. The addition of CD28 at the N-terminal of CD3ζ increases the overall rate of CD3ζ phosphorylation. Our computational model identifies that LCK phosphorylates CD3ζ through a mechanism of competitive inhibition. This model agrees with previously published data in the literature and predicts that phosphatases in this system interact with CD3ζ through a similar mechanism of competitive inhibition. This quantitative modeling framework can be used to better understand CAR signaling and T cell activation.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Rohrs JA,Zheng D,Graham NA,Wang P,Finley SDdoi
10.1016/j.bpj.2018.08.018subject
Has Abstractpub_date
2018-09-18 00:00:00pages
1116-1129issue
6eissn
0006-3495issn
1542-0086pii
S0006-3495(18)30970-6journal_volume
115pub_type
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