Signalling Pathways From Activating Receptors

As discussed above, many of the activating receptors in NK cells are associated with ITAM-containing adapter proteins through which they initiate signaling pathways. The receptors that do not associate with ITAM-containing proteins have novel ways of activating some of the same signaling pathways as the ITAM-containing receptors, via alternative mechanisms. Major pathways known to be activated by NK activating receptors include the PLCy pathway, the MAP kinase pathway, the PI3 kinase pathway, and the Rho/Rac GTPase pathway.

4.1. PLCy pathway

The activation of phospholipase C (PLC) y begins with the recruitment of the transmembrane adapter LAT to the phosphorylated ITAM [49], Once LAT itself is phosphorylated, it may recruit a variety of proteins through SH2 domains, including PLCy. During certain forms of NK cellmediated killing LAT is tyrosine phosphorylated [50]. However, in LAT' mice, NK cytotoxic function against certain tumours and via ADCC is normal [51]. These observations are consistent with the notion that redundant adapters may be able to replace or work in parallel with LAT in NK cells.

When PLCy is recruited by LAT to the receptor complex, it is then phosphorylated by ZAP-70 or Syk, giving it the ability to cleave the membrane lipid phophatidylinositol-4,5-bisphosphate (PIP7) to generate inositol-1,4,5-trisphosphate (IP ) and diacylglycerol (DAG). IP3 drives an increase in the intracellular concentration of Ca2+. This increase in Ca2+ concentration is required for granule release, and it drives transcriptional changes by controlling the activation of Ca2+-

sensitive transcription factors such as NFAT. DAG and the rise in Ca2+ recruit protein kinase C (PKC), which is involved both in the development of cytotoxicity and the phosphorylation of a variety of proteins involved in cell growth and differentiation, such as the MAP kinases.

4.2. MAP kinase pathway

MAP kinases play many roles in the immune response [reviewed in 52]. Generally speaking, MAP kinases in lymphocytes are involved in altering gene expression and thereby altering lymphocyte function. In NK cells, MAP kinases similarly amplify, transduce, and integrate signals from a variety of stimuli. However, in contrast to their role in other lymphocytes, MAP kinases in NK cells may also drive cytotoxic function without requiring transcriptional change [18,53-55]. This novel function may represent an alternative means of using the same signaling molecules to facilitate a more immediate response.

In another departure from other types of lymphocytes, NK cells activate a Ras-independent MAP kinase pathway [56]. While IL-2 activates a Ras-dependent pathway, ligation of targets activates a Ras-independent pathway that drives lytic function. The exact pathways by which MAP kinase is activated in NK cells are still under investigation, and further work will serve to clarify these differences in function and activation.

4.3. PI3K pathway

Phosphatidylinositol 3-kinase (PI3K) is an enzyme that, when recruited to the membrane, adds a phosphate to the inositol ring of phosphoinositides. The lipid products of PI3K phosphorylation affect a variety of targets, including guanine nucleotide exchange factors for the Rho/Rac GTPases, PKC, PLC, and a variety of protein kinases. In turn, a variety of cellular processes such as cell survival, proliferation, and migration may be controlled [reviewed in 57], PI3K may be activated downstream of proximal protein tyrosine kinase activation, or, in the case of NKG2D/DAP10 activation, it may bind directly to the receptor [44], The importance of PI3K in NK cell signaling is undisputed, but its exact role has not been determined. PI3K is involved in the regulation of several forms of NK cell cytotoxicity. ADCC and, in some instances, natural cytotoxicity are sensitive to PI3K inhibitors. PI3K may play a role upstream of the MAP kinase pathway [54,55],

4.4. Rac/Rho family of GTPases

Rac and Rho GTPases are GTP-binding proteins that act as molecular switches. When bound to GTP, the GTPases can interact with effector or target molecules and initiate signaling; however, when they are bound to GDP, this signal transduction is abrogated. The members of the Rac/Rho family have intrinsic GTPase activity, but cycling between the GTP- and GDP-bound states is also regulated by a large number of guanine nucleotide exchange factors (GEFs) [reviewed in 58],

The importance of the Rac/Rho family of GTPases in actin cytoskeleton organization is well known; furthermore, evidence of a significant role for these small GTPases and their exchange factors in a variety of signaling pathways is emerging [reviewed in 59]. The Rac/Rho GTPases have been found to play a role in signaling that activates transcription factors and cell cycle progression. In NK cells, the Rac/Rho GTPases and their exchange factors help regulate cytotoxicity [16,17,60]. For example, RhoA is involved in initiating the actin polarization necessary

ITIM'Containing inhibitory receptor

ITIM'Containing inhibitory receptor

Figure 3. Signals from inhibitory receptore. Liganrl binding to an inhibitory receptor results in ihc activation of Src family kinases, which phosphory laic [lie ITIM within the intracellular tail of the receptor. Once phosphory lated, the ITIM is able to recruit the phosphatase SHP-I through its SH2 domain, SHP-1 Is thought to act cither by dephospho-ry lating and thereby deactivating a single major substrate such as Vavl or by the dephosphorylation of a variety of substrates early in the activation cascade.

Figure 3. Signals from inhibitory receptore. Liganrl binding to an inhibitory receptor results in ihc activation of Src family kinases, which phosphory laic [lie ITIM within the intracellular tail of the receptor. Once phosphory lated, the ITIM is able to recruit the phosphatase SHP-I through its SH2 domain, SHP-1 Is thought to act cither by dephospho-ry lating and thereby deactivating a single major substrate such as Vavl or by the dephosphorylation of a variety of substrates early in the activation cascade.

for granule release. Moreover, the Rac/Rho family GEFs Vavl and Vav2 have been shown to control cell mediated killing by NK cells [16,17]. This family of molecules control both actin accumulation and lipid polarization to [he site of target cell contact, and other roles in signaling and granule delivery are likely.

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