Crosstalk (biology)

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

One example of crosstalk between proteins in a signalling pathway can be seen with cyclic adenosine monophosphate's (cAMP) role in regulating cell proliferation by interacting with the mitogen activated protein (MAP) kinase pathway. cAMP is a compound synthesized in cells by adenylate cyclase in response to a variety of extracellular signals. cAMP primarily acts as an intracellular second messenger whose major intracellular receptor is the cAMP dependent protein kinase (PKA) that acts through the phosphorylation of target proteins. The signal transduction pathway begins with ligand receptor interactions extracellularly. This signal is then transduced through the membrane, stimulating adenylyl cyclase on the inner membrane surface to catalyze the conversion of ATP to cAMP. cAMP can inhibit ERKs in a variety of ways, most of which involve the cAMP dependent protein kinase (PKA) and the inhibition of Ras dependent signals to Raf 1. However, cAMP can also stimulate cell proliferation by stimulating ERKs. This occurs through the induction of specific genes via phosphorylation of the transcription factor CREB by PKA. For example, integrin mediated cytoskeleton assembly and even cell motility are affected by the physical state of the ECM. This cleavage in turn activates PKA by exposing the catalytic sites of the C subunits, which can then phosphorylate an array of proteins in the cell. In this case, cAMP serves to inhibit immunity players. PKA type I colocalizes with the T cell and B cell antigen receptors and causes inhibition of T and B cell activation. PKA has even been highlighted as a direct inducer of genes contributing to immunosuppression. Additionally, the cAMP pathway also interacts with the MAPK pathway in a more indirect manner through its interaction with hematopoietic PTPase (HePTP). HePTP is expressed in all leukocytes. When overexpressed in T cells, HePTP reduces the transcriptional activation of the interleukin 2 promoter typically induced by the activated T cell receptor through a MAPK signaling cascade. The way that HePTP effectively inhibits the MAPK signaling is by interacting with the MAP kinases Erk1, Erk2, and p38 through a short sequence in HePTP's non catalytic N terminus termed the kinase interaction motif (KIM)., The highly specific binding of Erk and p38 to this subunit of HePTP results in rapid inactivation of the signaling cascade (see figure 3). Yet, since both HePTP and Erk are cytosolic enzymes, it is reasonable to conclude that there exists a mechanism for the inhibition of Erk by HePTP to cease in order to allow for the translocation of activated Erk to the nucleus. Indeed, like in many other cases of protein protein interaction, HePTP appears to be phosphorylated by Erk and p38 at the sites Thr45 and Ser72. Thus, it seems plausible that PKA in the cAMP pathway could even be further involved in the regulation of lymphocyte activation not only by inhibiting the antigen receptor MAPK signal pathway at its final stage, but even further upstream.