# Regulation of Protein Kinase C Theta by Phosphorylation

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $41,376

## Abstract

PROJECT SUMMARY
The overall vision of the proposed research is to gain a comprehensive understanding of how phosphorylation
regulates the activity and function of a key regulator of immune signaling, the Ser/Thr protein kinase C (PKC)
Theta (). This kinase is selectively expressed in hematopoietic cells where it transduces signals resulting in T
cell and platelet activation.1,2 Its dysregulation is associated with a variety of pathophysiological conditions
including blood cancers,3,4 inflammatory diseases,5 thrombosis,6 and hemostasis.7 Despite this, the regulation
and function of PKC remains largely unknown and necessitates further investigation. Phosphorylation of PKC
plays an essential role in regulating its maturation, catalytic activity, and subcellular localization,8 all of which are
crucial for PKC function in T cells and platelets. This proposal aims to understand how phosphorylation at
known conserved priming sites (activation loop, turn motif, hydrophobic motif),9 a bioinformatically-identified new
potential priming site (Ser662), and an uncharacterized activation-induced site (Ser685), regulate the maturation,
activity, and/or localization of PKC. Unbiased phosphoproteomics approaches have revealed that
phosphorylation of Ser685 significantly increases in T cells10 and platelets11 in response to stimulation, however
its function has not yet been determined due, in part, to a lack of available research tools. This site, and Ser662
are positioned on a key regulatory segment, the C-tail, and are evolutionarily conserved. The central hypothesis
driving this proposal is that phosphorylation of S662 is involved in the maturation of PKC and that activation-
induced phosphorylation of S685 promotes the re-autoinhibition of activated PKC to facilitate signal termination.
To this end, I will investigate how nonphosphorylatable or phosphomimetic mutations at these residues impact
PKC biochemical properties, cellular activity, subcellular localization, and downstream signaling (Aim 1).
Additionally, I will examine the phosphoproteome of PKC in Jurkat cells and platelets and examine how
phosphorylation at the agonist-induced site, Ser685, affects downstream signaling. I will also aim to identify the
kinase(s) regulating PKC Ser685 phosphorylation using various phosphoproteomics approaches (Aim 2).
These key studies will elucidate the functional impact of PKC phosphorylation at critical residues and how this
influences downstream signaling. Moreover, this proposal will elucidate substrates and signaling networks
regulated by PKC. Uncovering the regulation and function of PKC, a key regulator of T cells and platelets, is
crucial to understanding T cell and platelet signaling in both normal and disease states.

## Key facts

- **NIH application ID:** 10917063
- **Project number:** 5F31HL168916-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Stefanie Jill Hodapp
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,376
- **Award type:** 5
- **Project period:** 2023-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917063

## Citation

> US National Institutes of Health, RePORTER application 10917063, Regulation of Protein Kinase C Theta by Phosphorylation (5F31HL168916-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10917063. Licensed CC0.

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