Signal transmission can be short or long through the activation of another cascade, direct or indirect. An example of a short cascade is the STAT path. Here, after aggregation of growth factor receptors, the associated JAK-protein kinases are activated by transfosporilation. Activated JAK kinases directly activate transcription factors, STAT-proteins localized in cytoplasm (Shemarova, 2003). In the embryonic ectoderm of drosophila, the Hh signal is also transmitted over a short distance and is limited to nearby cells. At the border of each embryo segment, the HS protein is secreted by a narrow band of cells and acts as a morphogen that determines positional information in the segments. The transcription of the wingless (wg) gene is supported in one part of the neighboring cells, and the expression of the Serrate (Ser) gene is suppressed in the other part (Mohler and Vani, 1992; Hatini and DiNardo, 2001).
An example of a branched complex pathway is the Ras/MAP-kinase cascade. Cascade activators are autophosphorylated regulatory kinases. The polyfunctional enzyme MAP-kinase phosphorylates and activates cytoplasmic, membrane, and nuclear proteins, turning them into transcription factors (Shemarova, 2003). In the Imaginal disc of the drosophila wing, positional determination occurs as a result of the long-range effect of the Hh ligand. Hh secreted by the rear compartment cells spreads through several cell rows to the front compartments, forming a concentration gradient. In this context, Hh activates different target genes by the type of dose-dependence not only in nearby cells. Cells respond differently to the presence of Hh depending on their position in the morphogenetic gradient and signal intensity: they activate or repress different gene combinations and form different cell types, including different differentiation programs (Vervoort, 2000). In frogs, fish, chickens, and mice, the Shh protein, which is related to Hh, also acts at a considerable distance from its site of secretion.
By forming a concentration gradient in the ventral part of a neutral tube or limb embryo through dozens of cell diameters, Shh activates or represses different groups of transcription regulators, determines the direction of cell differentiation or the formation of anteroposterior polarity (Zeng et al., 2001). In a developing embryo, Wg proteins can also act within a short and long-distance, spreading across different tissues at a distance of several cell diameters from the site of synthesis. The pattern of gene expression in cells responding to the signal depends on the concentration of Wg (Neumann and Cohen, 1997). The results of signal induction significantly depend on the interaction between the cascades. Different signaling systems communicate with each other via lateral transmission chains, which occur at many stages of transduction, activating each other with intermediate products. To date, many facts are known about the mutual influence of signaling pathways. For example, Hh-, Dpp-, and EGFR-cascades interact in drosophila during the development of the wing (Crozatier et al., 2002); RAS/MAPK- and EGFR-pathways participate in the specialization of leg cells (Alamo et al., 2002); EGFR and Wg signaling systems are associated with the development of renal tubules (Sudarsan et al., 2002).
There is no clear understanding of the specific molecular mechanisms of these interactions. However, the possibility of a network of signaling pathways may be determined by some properties of signaling proteins. Thus, the same ligands can bind to different receptors and activate alternative cell development pathways. Such ambiguous actions may be a consequence of alternative splicing of the corresponding genes' transcripts and the formation of many independent isoforms of ligands and receptors with altered extracellular domains (Missler and Sudhof, 1998). In turn, the same receptor in different tissues may activate different intracellular transmitters.
Multiple signaling pathways may be involved in the regulation of target genes expression simultaneously, forming a common signal protein or acting together on different modules of gene encoders, and the same signals may cause different patterns of expression. Active confirmation of transcription factors can be formed simultaneously by protein kinases from different signal systems. Finally, the specificity of the response may depend on the compartmentalization of the signal on the cell surface (Tarchevsky, 2000; Millor, Altaba, 2002; Pires-daSilva, 2003).