Signaling through sphingolipid microdomains of the plasma membrane: The concept of signaling platform

Transmembrane signaling requires modular interactions between signaling pro teins, phosphorylation or dephosphorylation of the interacting protein part ners [1] and temporary elaboration of supramolecular structures [2], to con vey the molecular information from the cell surface to the nucleus. Such si gnaling complexes at the plasma membrane are instrumental In translating th e extracellular cues into intracellular signals for gene activation. In the most straightforward case, ligand binding promotes homodimerization of the transmembrane receptor which facilitates modular interactions between the receptor's cytoplasmic domains and intracellular signaling and adaptor prot eins [3]. For example, most growth factor receptors contain a cytoplasmic p rotein tyrosine kinase (PTK) domain and ligand-mediated receptor dimerizati on leads to cross phosphorylation of tyrosines in the receptor's cytoplasmi c domains, an event that initiates the signaling cascade [4]. In other sign aling pathways where the receptors have no intrinsic kinase activity, intra cellular nonreceptor PTKs (i.e. Src family PTKs, JAKs) are recruited to the cytoplasmic domain of the engaged receptor. Execution of these initial pho sphorylations and their translation into efficient cellular stimulation req uires concomitant activation of diverse signaling pathways. Availability of stable, preassembled matrices at the plasma membrane would facilitate scaf folding of a large array of receptors, coreceptors, tyrosine kinases and ot her signaling and adapter proteins, as it is the case in signaling via the T cell antigen receptor [5]. The concept of the signaling platform [6] has gained usage to characterize the membrane structure where many different me mbrane-bound components need to be assembled in a coordinated manner to car ry out signaling. The structural basis of the signaling platform lies in pr eferential assembly of certain classes of lipids into distinct physical and functional compartments within the plasma membrane [7,8]. These membrane m icrodomains or rafts (Figure 1) serve as privileged sites where receptors a nd proximal signaling molecules optimally interact [9]. In this review, we shall discuss first how signaling platforms are assembled and how receptors and their signaling machinery could be functionally linked in such structu res. The second part of our review will deal with selected examples of raft -based signaling pathways in T lymphocytes and NK cells to illustrate the w ays in which rafts may facilitate signaling.