Mechanical regulation of PKA function in cell adhesion and migration
Active Project Grant Awarded Last action
- Award ID
- R35GM153456
- Recipient
-
University Of Vermont & State Agricultural College UEI Z94KLERAG5V9
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,184,245
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 46% complete
- Place of performance
- Burlington, VT 05405, USA
Award details come from USAspending.gov.
Description
- Abstract
- Cell adhesion to the extracellular matrix (ECM) is fundamentally important to multicellular life. Focal adhesions (FAS) are the best characterized cellular structures involved in cell-ECM adhesion, and not only serve as physical couplings but are important centers of signal transduction. While FAS are well- known and well- characterized for being enriched in tyrosine phosphorylated proteins, the phosphoserine and phosphothreonine content of FAS is three times higher than phosphotyrosine. Despite this, the kinases that mediate these modifications and the mechanisms and consequences of their function are poorly understood. We have found that the camp-dependent protein kinase (PKA), a venerable kinase with hundreds of targets throughout the cellular landscape, is present and active within FAS. Moreover, we have found that PKA binds directly to talin, a critically important mechanosensitive FA scaffolding protein, in a manner that requires conformational unfolding of talin. These observations suggest that talin is a mechanically-gated a-kinase anchoring protein (akap) that couples cellular tension to PKA signaling within FAS. Here, we propose to use biophysical, biochemical, and cell biological approaches to characterize the regulation and function of this new axis of localized mechanotransduction. We will delineate how (1) molecular and cellular mechanics regulate the PKA-talin interaction; (2) PKA-mediated phosphorylation regulates the function and interaction of talin, taps, and other FA proteins; (3) disrupting talin-PKA interaction and associated signaling events impact cell adhesion, cell spreading, and cell migration; and (4) cell adhesion and contractility regulate FA PKA activity. These investigations will not only reveal new facets of adhesion-dependent signal transduction, but will also identify FAS as a new, discrete niche for PKA function and establish a paradigm for mechanical regulation of this ubiquitous kinase that may play a role in other mechanosensitive cellular structures and events.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $370,892 | |
| Amendment | $370,892 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $147,487 | |
| Amendment | $147,487 | |
| Original award | $147,487 |
Quick answers
Who received award R35GM153456?
R35GM153456 was awarded to University Of Vermont & State Agricultural College by National Institute of General Medical Sciences (National Institutes of Health) on August 1, 2024.
How much is award R35GM153456 worth?
$1,184,245 has been obligated on R35GM153456.
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