Distinct Features of Doublecortin as a Marker of Neuronal Migration and Its Implications in Cancer Cell Mobility

Abstract

Neuronal migration is a critical process in the development of the nervous system. Defects in the migration of the neurons are associated with diseases like lissencephaly, subcortical band heterotopia (SBH), and pachygyria. Doublecortin (DCX) is an essential factor in neurogenesis and mutations in this protein impairs neuronal migration leading to several pathological conditions. Although, DCX is capable of modulating and stabilizing microtubules (MTs) to ensure effective migration, the mechanisms involved in executing these functions remain poorly understood. Meanwhile, there are existing gaps regarding the processes that underlie tumor initiation and progression into cancer as well as the ability to migrate and invade normal cells. Several studies suggest that DCX is involved in cancer metastasis. Unstable interactions between DCX and MTs destabilizes cytoskeletal organization leading to disorganized movements of cells, a process which may be implicated in the uncontrolled migration of cancer cells. However, the underlying mechanism is complex and require further clarification. Therefore, exploring the importance and features known up to date about this molecule will broaden our understanding and shed light on potential therapeutic approaches for the associated neurological diseases. This review summarizes current knowledge about DCX, its features, functions, and relationships with other proteins. We also present an overview of its role in cancer cells and highlight the importance of studying its gene mutations.

Keywords: CSC-cancer stem cells; DCX-doublecortin; GBM-glioblastoma multiforme; MAP-microtubule-associated protein; MT-microtubule; NSC-neural stem cells.

Figure 1

MTs are hollow tubes made of pfs, each of which is made of α and β-tubulin monomers tightly bound together in an organized conformation. Both monomers are composed of GTP molecules. This fig. shows DCX binding to the tubulin monomers at the MT plus-end of the β-tubulin (which possesses the hydrolyzed GDP) fitting into the inter-pf valley. DCX stabilizes MT, promotes bundling, and favors MT polymerization (Moores et al., 2003).

Figure 2

Neuronal migration involves polarization of the cytoskeleton. MTs can induce and/or maintain polarity. Abnormal cell migration likely reflects a faulty mechanism in cell polarization. 1. Microtubule polymerization and depolymerization (enlarged view of interactions between DCX and MTs). 2. Actin filament polymerization (enlarged view of the leading process). Reduction in DCX destabilizes MTs in vitro leading to polarization impairment. The “doublecortin regulators” act on DCX to aid effective migration. Kinases can phosphorylate DCX on its serine/threonine residues to aid migration of neuroblast, as phosphorylation of DCX is required for localization of the MTs and proper neuronal migration. However, these kinases (in red) are in free-flow in cancer cells and may be carcinogenic. Cancer cells may take advantage of these kinases to destabilize the MTs and promote uncontrolled movement of cells. While DCX is phosphorylated on the MTs, it can also bind to actin filaments at the leading process via spinophilin (gold). This promotes polymerization of actin and improves cellular migration.

Figure 3

Major human paralogs of DCX. All paralogs illustrated here have two DC domains (N-DC depicted in yellow, C-DC in orange). Two of the four isoforms of DCLK are represented: DCX-like and full-length DCLK, which has a kinase domain (green). DCLK full-length has a very close homolog called DCK2. The serine/proline-rich domain is colored blue (Fourniol et al., 2013).