Heterotrimeric G Proteins and the Regulation of Microtubule Assembly [chapter]

Sukla Roychowdhury, Jorge A. Sierra-Fonseca
2017 Cytoskeleton - Structure, Dynamics, Function and Disease  
Microtubules (MTs), a major component of cell cytoskeleton, exhibit diverse cellular functions including cell motility, intracellular transport, cell division, and diferentiation. These functions of MTs are critically dependent on their ability to polymerize and depolymerize. Although a signiicant progress has been made in identifying cellular factors that regulate microtubule assembly and dynamics, the role of signal transducing molecules in this process is not well understood. It has been
more » ... od. It has been demonstrated that heterotrimeric G proteins, which are components of G protein-coupled receptor (GPCR) signaling pathway, interact with microtubules and play important roles in regulating assembly/dynamics of this cytoskeletal ilament. While α subunit of G proteins (Gα) inhibits microtubule assembly and accelerates microtubule dynamics, Gβγ promotes tubulin polymerization. In this chapter, we review the current status of G-protein modulation of microtubules and cellular and physiological aspects of this regulation. Molecular, biochemical, and cellular methodologies that have been used to advance this ield of research are discussed. Emphasis has been given on G-protein-microtubule interaction in neuronal diferentiation as signiicant progress has been made in this ield. The outcome from this research relects the importance of GPCRs in transducing extracellular signals to regulate a variety of microtubule-associated cellular events. associate laterally to form the microtubule, a 25-nm-wide hollow cylindrical polymeric structure [1] . Due to the asymmetry of the αβ-tubulin heterodimer, MTs are polar structures with two distinct ends. These ends possess diferent polymerization rates: a slow-growing minus end with an exposed α-tubulin subunit, and a fast-growing plus end, at which the β-tubulin subunit is exposed [2, 3] . MT assembly occurs in two phases: nucleation, which is facilitated by a third tubulin isoform, γ-tubulin; and elongation, during which αβ-tubulin heterodimers are added to the plus end [1, 4] . Tubulin is a unique guanine nucleotide-binding protein containing one exchangeable binding site and one nonexchangeable binding site. GTP at both sites is needed for optimal assembly, and GTP at the exchangeable site is hydrolyzed after assembly [5, 6] . This hydrolysis creates an MT consisting largely of GDP-tubulin; however, a small region of GTP-bound tubulin, called a "GTP cap," remains at the end. This cap allows MTs to polymerize. The loss of the cap results in a transition from growth to shortening (called a "catastrophe"), whereas the reacquisition of the GTP cap results in a transition from shortening to growing (called a "rescue"). This behavior, known as dynamic instability, allows MTs to be remodeled rapidly in cells. An important consequence of dynamic instability is that it allows microtubules to search for speciic target sites within the cell more efectively [7] [8] [9] . The MT assembly process is depicted in Figure 1 . MT assembly and stability can be afected by a wide variety of proteins. In this regard, microtubule-associated proteins (MAPs) play a very important role. Members of this group of proteins, such as MAP2 and tau, are known to promote MT assembly and stabilize MTs in vivo and in vitro [10] [11] [12] [13] . The phosphorylation of MAPs is critical for their function, since Figure 1 . Polymerization/depolymerization of MTs. MTs is polymerized from tubulin heterodimer consisting of α and β subunits. A third tubulin isoform, γ-tubulin, serves as a template for nucleation, which allows proper MT assembly. As shown in the igure, MT assembly requires tubulin to be in GTP bound form. However, it is hydrolyzed to GDP when it is incorporated in MTs, except at the plus (+) end where tubulin remains at GTP bound form (a GTP cap). This cap allows MTs to polymerize. The loss of GTP cap (by hydrolysis) results in the transition to MT depolymerization (a "catastrophe"). GTP cap can be regained by binding to tubulin-GTP and MT polymerization is reestablished (a "rescue").
doi:10.5772/66929 fatcat:n2yl7z3bwbcfvethcuzbphshiu