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Various other signaling and adhesion molecules have been implicated in MTOC
repositioning. These include the already mentioned small G proteins, Rac, Cdc42,
Vav, and Fyn. In addition, the calcium-dependent tyrosine kinase Pyk-2 (RAFTK)
has been implicated in MTOC movements in NK cells (Sancho et al. 2000 ). One of
the molecules associated with Pyk-2 is paxillin which has also been implicated in
MTOC repositioning (Robertson and Ostergaard 2011 ; Avraham et al. 2000 ).
At present, the most compelling evidence for a signal closely linked to MTOC
repositioning is the activation of PKC. Two studies by Quann and colleagues show
that localized formation of diacylglyercol by flash photolysis lead to localized
accumulation of dynein at the site of photolysis followed by recruitment of the
MTOC (Quann et al. 2009 ). In their studies, calcium was not required. This
movement apparently required activation PKC-h followed by either PKC-e or
PKC-g (Quann et al. 2011 ).
21.5 Movement of Secretory Vesicles Towards the MTOC
T cell, and in particular CTL, vesicles contain perforin that forms holes in the target
cell membrane and granzymes that trigger apoptosis (Podack and Konigsberg 1984 ;
Pasternack et al. 1986 ; Tschopp and Nabholz 1990 ; Podack 1992 ; Trapani 2001 ;
Hoves et al. 2010 ). These vesicles have been characterized as ''secretory lysosomes''
(Blott and Griffiths 2002 ; Bossi and Griffiths 2005 ). In CTLs, trafficking of these
vesicles to the synaptic interface is regulated by two principal movements
(Fig. 21.1 ). The first is dynein-dependent movement of vesicles to the minus end
of microtubules, i.e., toward the microtubule-organizing center (MTOC) (Mentlik
et al. 2010 ), and the second is MTOC repositioning to the CTL contact surface
(Stinchcombe et al. 2006 ; Poenie et al. 2004 ). Both movements occur after CTL
recognition of antigen on the target cell and are initiated by proximal TCR signaling
(Sykulev 2010 ).
As discussed in the previous section, activated phospholipase C (PLCc) cleaves
PIP 2 resulting in the production of DAG and IP 3 and activation of protein kinase C
(PKC). While PKC appears to regulate MTOC movements, a rise in intracellular
Ca 2+ concentration regulates dynein-dependent granule movement toward the
MTOC. Dynein motors can function in the absence of Ca 2+ in a cell-free system
(Gennerich et al. 2007 ) indicating that Ca 2+ exercises its activity indirectly, and the
precise nature of the downstream events is not understood. However, recent data
provide evidence that the kinetics of intracellular Ca 2+ accumulation determines
how rapidly the dynein translocates the granules toward MTOC (Beal et al. 2009 ).
This is in accord with the analysis of granule movement in another system,
crustacean chromatophores, showing that a rise in intracellular Ca 2+ concentration
increases the dynein-mediated aggregation velocity of pigment granules by 4.4-
fold (Ribeiro and McNamara 2007 ). Thus, the two movements responsible for
intracellular granule trafficking are independently regulated by Ca 2+ - and DAG-
dependent signaling (Beal et al. 2009 ).
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