# Mechanisms controlling the inactivation of microtubule organizing center function at the centrosome

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $315,400

## Abstract

Project Summary/Abstract
The centrosome acts as a microtubule organizing center (MTOC), orchestrating microtubules into the mitotic
spindle through its pericentriolar material (PCM). This activity is biphasic, cycling through assembly and
disassembly during the cell cycle. Upon cell differentiation, MTOC activity at the centrosome is often
maintained in an inactive state as MTOC function is reassigned to non-centrosomal sites to accommodate
different cell functions. Although hyperactive centrosomal MTOC activity is a hallmark of some cancers and
has been linked to invasive cell behavior, little is known about how the centrosome is inactivated as an MTOC
either during mitotic exit or maintained in an inactive state in differentiated cells. We are using C. elegans as a
model to understand these fundamental knowledge gaps in MTOC biology in a live organism. Our analysis of
endogenous PCM proteins in C. elegans revealed that the PCM is composed of distinct protein territories
organized into an inner and outer sphere that are removed from the centrosome at different rates and using
different behaviors. We found that phosphatases oppose the addition of PCM by mitotic kinases, ultimately
catalyzing the dissolution of inner sphere PCM proteins at the end of mitosis. The nature of the PCM appears
to change such that the remaining aging PCM outer sphere is ruptured into sub-PCM ‘packets’ by microtubule
based cortical pulling forces. Thus, the centrosome appears to be inactivated as an MTOC by a two-step
mechanism beginning with PCM dissolution, followed by mechanically controlled rupture. In the proposed
research, we will uncover the mechanisms underlying this two-step model for the inactivation of MTOC function
at the centrosome. We will determine the mechanisms underlying PCM dissolution, identifying the pertinent
phosphatases, their targets at the centrosome, and the role of the removal of these targets in disassembly
(Aim 1). We will then specifically uncover the protein-protein interactions underlying the PCM outer sphere and
packets (Aim 2). Finally, we will probe the mechanisms underlying the inactivation of MTOC function in
differentiated cells and test the role of centrosome inactivation in cell differentiation (Aim 3). Proper microtubule
organization is essential for normal development and cell function and hyperactive MTOC function at the
centrosome is a hallmark of some cancers. Thus, the molecules uncovered in these studies could provide
potential therapeutic targets as well as shed light on this important, but understudied topic in cell and
developmental biology.

## Key facts

- **NIH application ID:** 9943937
- **Project number:** 1R01GM136902-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jessica Lynn Feldman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $315,400
- **Award type:** 1
- **Project period:** 2020-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9943937

## Citation

> US National Institutes of Health, RePORTER application 9943937, Mechanisms controlling the inactivation of microtubule organizing center function at the centrosome (1R01GM136902-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9943937. Licensed CC0.

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