Regulation of dynamic microtubules (MTs) is critical for cellular processes such as cell division, cell migration, cell polarity, organelle movements and nuclear positioning. Understanding conserved mechanisms of MT regulation are highly relevant to human biology and diseases such as cancer, neuronal diseases and wound healing. In this grant, we aim to elucidate fundamental conserved mechanisms responsible for MT regulation by studying MT plus end tracking proteins (+TIPs). These proteins coat the MT plus end and control the assembly, stability and disassembly of these polymers. In general, how these proteins work collectively to regulate MT dynamics in vivo is a pressing question in this active field. We study MT regulation using in vivo and in vitro approaches, using the fission yeast Schizosaccharomyces pombe as a tractable, simple model system. The XMAP215/Alp14 family of +TIPs is emerging as one of the most important of the +TIPs. These tubulin-binding proteins function as MT polymerases that add tubulin onto the ends of growing MT. Our preliminary results suggest that it has additional functions in MT nucleation and disassembly.
Our specific aims are: 1) To define how Alp14 works with gamma tubulin complex for MT nucleation; 2) To determine how Alp14 and the kinesin-8 Klp5/6 regulate the disassembly of MTs; 3) To elucidate the molecular mechanisms of how XMAP215/Alp14 proteins interact with tubulin to regulate MT dynamics.

Public Health Relevance

Microtubules are hollow protein tubes within cells that grow and shrink to move cellular components, shape the cell, and bring about cell division. In this grant, we study a key protein that binds to the very end of the microtubule in order to regulate the growth and shrinkage of these tubes. These studies will have broad relevance to human diseases such as cancer, stem cells and neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM115185-03
Application #
9316669
Study Section
Special Emphasis Panel (ZRG1-CB-R (02)M)
Program Officer
Gindhart, Joseph G
Project Start
2015-03-01
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$350,796
Indirect Cost
$122,852
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118