Role of NuMA in vertebrate cells: review of an intriguing multifunctional protein.

The 236 kDa large coiled-coil protein NuMA plays diverse important roles in vertebrate cells. It is an important component of the nuclear matrix in interphase cells, and is possibly involved in nuclear re-assembly after mitosis. In dividing cells, upon phosphorylation, NuMA disperses into the cytoplasm, associates with cytoplasmic dynein/dynactin to form a complex, and translocates along microtubules to the spindle poles where it organizes and tethers microtubules to spindle poles. It is thought that the stable complex of NuMA/dynein/dynactin is needed to focus microtubule minus ends to the spindle poles. But, it has also been reported that NuMA can organize microtubules in the absence of centrosomes and dynein. Another hypothesis suggests that once localized to the spindle poles, spindle-associated NuMA's exchange with cytoplasmic soluble pools and its stable crosslinking with the microtubule fibers are independent of dynein/dyactin. NuMA's function in spindle microtubule organization is regulated by RanGTP and Pins-related protein LGN. NuMA becomes dephosphorylated, loses its association with dynein/dynactin, and releases from spindle poles after anaphase onset to allow spindle disassembly and reformation of interphase daughter nuclei. The cell-cycle-dependent phosphorylation of NuMA is regulated by the balanced activities of protein kinases and phosphatases. It has been shown that phosphorylation of NuMA by cyclin B/cdc2 kinase allows NuMA to release from the nucleus and to associate with centrosomes and/or microtubules at the spindle poles, while NuMA's dephosphorylation due to the cyclin B degradation allows NuMA to dissociate from the spindle poles after anaphase onset. Overexpression of NuMA interferes with spindle-associated dynein localization and promotes multipolar spindle formation and cancer. On the other hand, NuMA is absent in many kinds of non-proliferating cells and highly differentiated cells. NuMA also functions during meiotic spindle organization in male and female germ cells. Degradation of NuMA results in the breakdown of normal nuclear structure, and has been used as a marker of cell apoptosis. The implications of NuMA protein in somatic cell animal cloning by nuclear transfer are discussed.