The overall goal of the proposed research is to understand how the cytoplasmic tyrosine kinases Abl and Arg regulate actin remodeling downstream of growth factor signals to control cell morphology and movements during early vertebrate development. Abl and Arg are members of a family of cytoplasmic tyrosine kinases that uniquely have actin-binding domains. They have been implicated in regulating cell shape and motility in several contexts, such as spreading and migration of fibroblasts and extension of neuritis in neurons. Abl and Arg are involved in processes that impact on human health and diseases, including for example microbial invasion and cancer progression. In depth understanding of the molecular mechanisms underlying the functions of Abl and Arg is thus important. In this project, gastrulation movements in African clawed frog Xenopus laevis will be used as the model system to assess the roles of Abl and Arg in morphogenesis. Studies carried out in this laboratory revealed that Arg modulated two types of cell motility during Xenopus gastrulation, that of head mesoderm migration and trunk mesoderm convergent extension. Arg regulated cell shapes and membrane protrusions and affected actin organization. Arg could phosphorylate two effector proteins CrkII and paxillin. Further research will be conducted to address the following hypotheses. 1) Receptor tyrosine kinases activate both Abl and Arg to control cell movements. 2) Abl and Arg crosstalk with non-canonical Wnt signals to modulate convergent extension. 3) CrkII acts as an effector of Abl and Arg to partially mediate their activities in gastrulation. 4) Abl and Arg modulate actin dynamics in both the head and the trunk mesoderm to influence cell morphology and motility. Data collected from these studies will provide crucial insight into mechanistic control of cell movements by Abl and Arg. Though research will be performed in Xenopus, results promise to help shed light on how Abl and Arg modulate cell behaviors in other contexts, such as in morphogenesis during mammalian embryogenesis and in cancer metastasis.

Public Health Relevance

Research proposed in this grant addresses the molecular mechanisms via which the cytoplasmic tyrosine kinases Abl and Arg control cell movements. Abl and Arg have been implicated in many processes that affect human health and diseases, including neuronal development, microbial invasion, and cancer progression. Data gathered from our studies will enhance our understanding on basic mechanisms underlying Abl and Arg function, help to add crucial insight in cancer metastasis and invasion, and contribute to the search for new therapeutic targets for metastatic cancers associated with impaired Abl and Arg signals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM098566-01A1
Application #
8368467
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
2012-08-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$322,300
Indirect Cost
$102,300
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294