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

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $186,291

## 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:** 10794831
- **Project number:** 3R01GM136902-04S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Jessica Lynn Feldman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $186,291
- **Award type:** 3
- **Project period:** 2020-08-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794831

## Citation

> US National Institutes of Health, RePORTER application 10794831, Mechanisms controlling the inactivation of microtubule organizing center function at the centrosome (3R01GM136902-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10794831. Licensed CC0.

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