Small molecule gated split-tyrosine phosphatases and orthogonal split-tyrosine kinases

Karla Camacho-Soto, Javier Castillo-Montoya, Blake Tye, Luca O. Ogunleye, Indraneel Ghosh

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Protein kinases phosphorylate client proteins, while protein phosphatases catalyze their dephosphorylation and thereby in concert exert reversible control over numerous signal transduction pathways. We have recently reported the design and validation of split-protein kinases that can be conditionally activated by an added small molecule chemical inducer of dimerization (CID), rapamycin. Herein, we provide the rational design and validation of three split-tyrosine phosphatases (PTPs) attached to FKBP and FRB, where catalytic activity can be modulated with rapamycin. We further demonstrate that the orthogonal CIDs, abscisic acid and gibberellic acid, can be used to impart control over the activity of split-tyrosine kinases (PTKs). Finally, we demonstrate that designed split-phosphatases and split-kinases can be activated by orthogonal CIDs in mammalian cells. In sum, we provide a methodology that allows for post-translational orthogonal small molecule control over the activity of user defined split-PTKs and split-PTPs. This methodology has the long-term potential for both interrogating and redesigning phosphorylation dependent signaling pathways.

Original languageEnglish (US)
Pages (from-to)17078-17086
Number of pages9
JournalJournal of the American Chemical Society
Volume136
Issue number49
DOIs
StatePublished - Dec 10 2014

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Phosphatases
Sirolimus
Phosphoric Monoester Hydrolases
Protein-Tyrosine Kinases
Protein Kinases
Tyrosine
Tacrolimus Binding Proteins
Proteins
Abscisic Acid
Molecules
Phosphoprotein Phosphatases
Dimerization
Signal Transduction
Signal transduction
Phosphorylation
Phosphotransferases
Acids
Catalyst activity
Cells
gibberellic acid

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Small molecule gated split-tyrosine phosphatases and orthogonal split-tyrosine kinases. / Camacho-Soto, Karla; Castillo-Montoya, Javier; Tye, Blake; Ogunleye, Luca O.; Ghosh, Indraneel.

In: Journal of the American Chemical Society, Vol. 136, No. 49, 10.12.2014, p. 17078-17086.

Research output: Contribution to journalArticle

Camacho-Soto, Karla ; Castillo-Montoya, Javier ; Tye, Blake ; Ogunleye, Luca O. ; Ghosh, Indraneel. / Small molecule gated split-tyrosine phosphatases and orthogonal split-tyrosine kinases. In: Journal of the American Chemical Society. 2014 ; Vol. 136, No. 49. pp. 17078-17086.
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