Figure 3. Protein kinase targets as components of intracellular signal transduction networks.

Glycogen synthase kinase 3 (GSK3) is an example of a widely distributed target that modulates diverse cellular functions. Death-associated protein kinase 1 (DAPK1) has a more restricted cellular role, but both are components of an integrated web of pathways. Selective biological responses are possible because such networks can transduce various cellular stimuli into an integrated response, through mechanisms that are incompletely understood. The target kinases represent network nodes, the quantitative importance of which is altered under conditions of deregulation. The activity of GSK3 is regulated by several mechanisms that allow selective phosphorylation of substrates in response to distinct input signals. The regulatory mechanisms include modulation of GSK3 activity by inhibitory serine phosphorylation and activating tyrosine phosphorylation of the enzyme, coordinated phosphorylation of its substrates, dynamic regulation of the subcellular distribution of GSK3 and the assembly of GSK3 into distinct multi-protein complexes for selective substrate phosphorylation. DAPK1 regulates signalling pathways that are important to cell survival and translational control through phosphorylations of a highly selective set of substrate proteins in response to its activation by distinct cellular stimuli, such as increased Ca²⁺ levels, which are sensed through its calmodulin (CAM) subunit. Examples of central nervous system functions that have been proposed for DAPK1 and GSK3 are shown in orange. Aβ, amyloid-β; BAX, BCL2-associated X protein; CAMK1, Ca²⁺–calmodulin-dependent protein kinase 1; CAMKK, CAMK kinase; C/EBP, CCAAT/enhancer-binding protein; CREB, cyclic AMP response element binding protein; ECM, extracellular matrix; EIF2B, eukaryotic initiation factor 2B; ERK, extracellular signal-regulated kinase; HSF1, heat shock factor 1; IRS1, insulin receptor substrate 1; JNK, Jun I-terminal kinase; MAP1B, microtubule-associated protein 1B; MAPK, mitogen-activated protein kinase; MLC, myosin light chain; MRPL13, mitochondrial ribosomal protein L13; MRPS6, mitochondrial ribosomal protein S6; MYC, myelocytomatosis viral oncogene homologue; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor κB; phospho–S, phosphorylated serine; phospho–Y, phosphorylated tyrosine; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PKC, protein kinase C; PKD, protein kinase D; PYK2, proline-rich tyrosine kinase 2; TP53, tumour protein p53; RPS6KA1, ribosomal protein S6 kinase, 90kDa, polypeptide 1.