Pleiotropic functions of TAOK2 and its dysregulation in neurodevelopmental disorders

Abstract

Thousand and one amino acid kinases (TAOKs) are relatively understudied and functionally pleiotropic protein kinases that have emerged as important regulators of neurodevelopment. Through their conserved amino-terminal catalytic domain, TAOKs mediate phosphorylation at serine/threonine residues in their substrates, but it is their divergent regulatory carboxyl-terminal domains that confer both exquisite functional specification and cellular localization. In this work, we focus specifically on diverse functions of TAOK2 in the context of neurodevelopment and neurodevelopmental disorders. TAOK2 is the only member of the TAOK family with two coiled coiled domains instead of three, and the canonical isoform, TAOK2α, has a unique endoplasmic reticulum (ER) targeting domain and microtubule binding domain functioning to tether ER to microtubules. Its spliced isoform, TAOK2β, is less understood. The precise mechanisms underlying the role of TAOK2 in neurodevelopment and neurodevelopmental disorders are not clearly understood. Following up on previous work showing that TAOK2 phosphorylation of cytoskeletal protein Septin 7 is critical for dendritic spine maturation, in Chapter 2, we identify 14-3-3 proteins as downstream interacting proteins important for maintaining this phosphorylation. We have also identified changes in primary cilium length, trafficking, and signaling as potential mechanisms underlying copy number variation of 16p11.2, a genomic locus in which TAOK2 resides, in Chapter 3. Further, in Chapter 4, we lay preliminary work showing that autism associated TAOK2 mutations differentially affect the catalytic activity and localization. In summary, this work elucidates how TAOK2 contributes to neurodevelopment and associated disorders through its pleiotropic functions.