DCLK2

DCLK2 Full Name

doublecortin-like kinase 2

DCLK2 Introduction

DCLK2 (doublecortin-like kinase 2), also known as DCAMKL2, belongs to a small family of proteins that unite a microtubule-binding domain with a serine/threonine protein kinase, thereby linking the neuronal cytoskeleton to intracellular signaling. The family is named for doublecortin, the product of the DCX gene that is mutated in X-linked lissencephaly and double cortex syndrome; doublecortin-like kinases share the two doublecortin (DCX) domains that mediate microtubule binding and stabilization but add a kinase domain at their C-terminus. DCLK2 is expressed predominantly in the nervous system, where it contributes to the migration and differentiation of neurons and to the growth of their processes. By binding to microtubules, the DCX domains of DCLK2 stabilize these cytoskeletal polymers, while the kinase domain phosphorylates substrates that regulate microtubule dynamics and neuronal signaling, allowing the protein to coordinate cytoskeletal reorganization with the signaling events that drive neurite extension. DCLK2 can also influence gene expression through its interactions with components of the transcription machinery. Dysregulation of doublecortin-like kinases has been observed in neurological disorders and in some cancers, and members of the family have been investigated both as markers of neural progenitor cells and as potential drug targets, particularly the related protein DCLK1 in gastrointestinal malignancies.

Figure 1. The structure of DCLK2.

Domain Composition and Microtubule-Binding Mechanism
DCLK2 is a modular protein whose N-terminal region contains two tandem doublecortin (DCX) domains, each of which adopts a ubiquitin-like fold specialized for binding microtubules.
The two DCX domains cooperate to recognize the microtubule lattice, and their binding stabilizes microtubules against depolymerization and promotes the bundling of microtubules in neurons.
Following the DCX domains is a serine/threonine kinase domain of the Ca2+/calmodulin-dependent protein kinase family, which is catalytically active and can autophosphorylate as well as phosphorylate exogenous substrates.
A C-terminal region and intervening linkers contain additional sites for protein-protein interactions and for regulation by phosphorylation.
The DCLK2 gene is located on human chromosome 4, and multiple splice variants are produced, some of which encode kinase-inactive isoforms that may act as dominant-negative regulators.
In neurons, DCLK2 localizes along microtubules in axons and dendrites, and its abundance is dynamically regulated during neural development.
The combination of a microtubule-binding module and a signaling kinase within a single polypeptide distinguishes DCLK2 from most other microtubule-associated proteins.

Neuronal Migration, Process Outgrowth, and Disease Relevance
During cortical development, doublecortin family proteins are required for the migration of neurons from the ventricular zone to their final positions, and defects in their function cause severe brain malformations.
DCLK2 contributes to the stabilization of microtubules in growing axons and dendrites, supporting the extension and branching of neuronal processes that establish the connectivity of the nervous system.
In cultured neurons, manipulation of DCLK2 expression alters neurite outgrowth and the dynamics of the growth cone, the structure at the tip of a growing axon that senses guidance cues.
The kinase activity of DCLK2 allows extracellular signals to influence microtubule behavior, coupling receptor-mediated signaling to cytoskeletal reorganization during neuronal differentiation.
Expression of DCLK2 is enriched in populations of neural progenitor cells and immature neurons, and family members are used experimentally as markers of neurogenesis.
Altered expression of doublecortin-like kinases has been reported in brain tumors and in other cancers, where the proteins may influence tumor cell migration, and the related kinase DCLK1 has attracted particular attention as a marker of cancer stem cells in the gastrointestinal tract, prompting efforts to develop selective inhibitors.

Alternate Names for DCLK2

DCLK2; doublecortin-like kinase 2; CL2; DCK2; CLIK2; DCDC3; CLICK2; DCDC3B; DCAMKL2; CLICK-II; serine/threonine-protein kinase DCLK2; CaMK-like CREB regulatory kinase 2; doublecortin and CaM kinase-like 2; doublecortin-like and CAM kinase-like 2; doublecortin domain-containing protein 3B