Integrins play important roles in basic cellular functions such as adhesion, growth, and migration as well as specialized functions in platelet plug formation during hemostasis and in T cell mediated immune responses. Abnormal expression and hyperactivity of integrins leads to cardiovascular diseases, impaired inflammatory responses, T cell malfunction, and enhanced tumor metastasis. Current integrin inhibitors that block extracellular ligand binding often cause serious adverse effects. Our overall goal is to elucidate the molecular mechanisms that activate integrins more specifically through the inside-out signaling pathway, thus facilitating the development of new therapies targeting this pathway. The main focus of this proposed study is to understand the structural basis of intermolecular interactions and intramolecular rearrangements that modulate integrin activity, thus altering cell adhesion and motility. The inside-out integrin signaling pathway has recently emerged as a new target for suppressing integrin activity. Integrin activation through this pathway is triggered by talin and mediated by a small GTPase, Rap1, and its effector protein RIAM (Rap1-interacting adaptor molecule). A co-activator, kindlin, also significantly enhanced the integrin activity. However, many key questions regarding how specific inter- and intra-molecular interactions regulate inside-out integrin activation remain unanswered. We have previously determined the structural basis of RIAM recruitment by Rap1 and the PM translocation and conformational activation of talin by RIAM. In this proposal, we aim to address the following central questions regarding the conformational rearrangement and specific interactions underlying the functional regulation of RIAM, talin, and kindlin: 1) to elucidate the structural basis of regulatory intramolecular interactions of RIAM and talin; 2) to determine the molecular basis of enhanced talin activity induced by the interaction of RIAM and talin; and 3) to probe the molecular mechanisms underlying the different integrin- regulating properties among kindlin isoforms and the co-localization of kindlin and talin in integrin signaling. Our studies will significantly advance the understanding of the regulatory mechanisms of integrin activation through the inside-out pathway.

Public Health Relevance

Integrin dysfunction has been linked to severe health conditions such as the development and metastasis of several types of tumors as well as cardiovascular and inflammatory diseases. We proposed to elucidate novel regulatory mechanisms in inside-out integrin signaling that activates integrins more specifically and potently. Our studies will provide important insights that facilitate the development of the new anti-integrin approaches that reduce the severe adverse effects caused by current integrin inhibitors for related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
1R35GM119560-01
Application #
9141784
Study Section
Special Emphasis Panel (ZRG1-CB-B (50)R)
Program Officer
Smith, Ward
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
1
Fiscal Year
2016
Total Cost
$446,250
Indirect Cost
$196,250
Name
Research Institute of Fox Chase Cancer Center
Department
Type
DUNS #
064367329
City
Philadelphia
State
PA
Country
United States
Zip Code
19111