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Author ORCID Identifier

https://orcid.org/0009-0000-6453-5950

Date Available

7-25-2028

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Arts and Sciences

Department/School/Program

Biology

Faculty

Chintan Kikani

Faculty

Jakub Famulski

Abstract

PAS kinase (PASK) is an evolutionarily conserved serine/threonine kinase characterized by an N-terminal PAS sensory domain and a C-terminal catalytic domain. It functions as a nutrient-responsive signaling protein. PASK is expressed in metabolically active tissues such as the liver, adipose tissue, pancreas, and brain, where it contributes to metabolic homeostasis by regulating glucose and lipid metabolism. In the context of stem cells, which are undifferentiated cells capable of self-renewal and differentiation into specialized cell types, PASK has been involved in the initiation of differentiation programs by linking nutrient availability to transcriptional regulation and is therefore considered a key regulator of cell fate decisions. Despite its importance, the structural mechanisms that regulate PASK activity, localization, and stability in response to nutrient signals remain unknown.

This dissertation investigates how the PASK function is regulated through coordinated control of its structural state to enable appropriate cellular response to metabolic cues. Using molecular, biochemical, and structural approaches, I identified a previously unrecognized PAS domain architecture in PASK, revealing that one of its PAS domains is discontinuous in sequence yet reassembles in three-dimensional space in response to nutrient cues. This structural reconstitution serves as a switch that stabilizes the kinase activation loop and facilitates PASK nuclear localization. These findings reveal a novel mode of sensory domain-mediated kinase regulation and provide insight into how metabolic signals are translated into transcriptional control.

Because PASK activity promotes differentiation, this prompted further investigation into how its function is restricted in self-renewing stem cells. Ongoing studies of PASK behavior during self-renewal suggest that its stability is regulated by competing post-translational modifications. Specifically, APC/C-mediated ubiquitylation promotes PASK degradation during proliferative expansion, whereas p300-dependent acetylation counters that process, resulting in PASK stabilization, which drives exit from self-renewal and progression towards differentiation commitment. Because PASK acetylation is linked with mitochondrial oxidation of glutamine, this emerging insight suggests a metabolic control of stem cell fate transition through dynamic control of PASK activity, subcellular localization, and stability.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.360

Archival?

Archival

Funding Information

This work was supported by funding from the National Institute of Health (R01AR073906).

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