Crosstalk (biology)

cAMP is a compound synthesized in cells by adenylate cyclase in response to a variety of extracellular signals.

However, the topography and mechanical properties of the ECM also come to play an important role in powerful, complex crosstalk with the cells growing on or inside the matrix.

[7] For example, integrin-mediated cytoskeleton assembly and even cell motility are affected by the physical state of the ECM.

[7] In turn, binding of the same integrin (α5β1) to an immobilized fibronectin ligand is seen to form highly phosphorylated focal contacts/focal adhesion (cells involved in matrix adhesion) within the membrane and reduces cell migration rates[7] In another example of crosstalk, this change in the composition of focal contacts in the cytoskeleton can be inhibited by members of yet another pathway: inhibitors of myosin light-chain kinases or Rho kinases, H-7 or ML-7, which reduce cell contractility and consequently motility.

Newly formed cAMP is released from the membrane and diffuses across the intracellular space where it serves to activate PKA.

[4] 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.

[4] In lymphocytes, the intracellular levels of cAMP increase upon antigen-receptor stimulation and even more so in response to prostaglandin E and other immunosuppression agents.

Phosphorylation of this third site by PKAs from the cAMP pathway inhibits binding of MAP kinases to HePTP and thereby upregulates the MAPK/ERK signaling cascade.

This prevents HePTP from binding to Erk and frees the MAPK pathway from inhibition, allowing downstream signaling to continue (see figure 4).

Figure 1: a possible mechanism of cAMP/PKA inhibition of ERK activation (MAPK pathway). cAMP activation of PKA activates Rap1 via Src. Rap1 then phosphorylates Ras and inhibits signaling to Raf-1.
Figure 2: the matrix can play into other pathways inside the cell even through just its physical state. Matrix immobilization inhibits the formation of fibrillar adhesions and matrix reorganization. Likewise, players of other signaling pathways inside the cell can affect the structure of the cytoskeleton and thereby the cell's interaction with the ECM.
Figure 3: even without activation by a ligand bound to the receptor (R1), the MAPK pathway normally shows basal activity (at low levels). However, HePTP counteracts this activity.
Figure 4: activation of the cAMP pathway by binding of ligand to its appropriate receptor (R2) leads to the activation of cAMP-dependent protein kinase (PKA) by adenylate cyclase (AC). This activated PKA then phosphorylates HePTP at Ser23, inhibiting its ability to bind to Erk and subsequently inhibit the MAPK pathway.