Crosstalk (biology)
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Biological crosstalk refers to instances in which one or more components of one signal
transduction pathway affect 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.
Contents
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1 Crosstalk Between Signaling Pathways
2 Transmembrane Crosstalk
3 Crosstalk in Lymphocyte Activation
4 Works Cited
Crosstalk Between Signaling Pathways[edit source |
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One example of crosstalk between proteins in a signaling 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.[1] 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.[2] 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.[3][4]
ERK, a participating protein in the MAPK signaling pathway, can be activated or
inhibited by cAMP.[5] 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.[6] 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.[5] Though ERKs do not appear to be a requirement
for this phosphorylation of CREB, the MAPK pathway does play into crosstalk again, as
ERKs are required to phosphorylate proteins downstream of CREB.[5] Other known
examples of the requirement of ERKs for cAMP-induced transcriptional effects include
induction of the prolactin gene in pituitary cells, and of the dopamine beta-hydroxylate
gene in pheochromocytomal cells (PC12).[6] A number of diverse mechanisms exist by
which cAMP can influence ERK signaling. Most mechanisms involving cAMP inhibition
of ERKs uncouple Raf-1 from Ras activation through direct interaction of PKA with Raf1 or indirectly through PKA interaction with the GTPase Rap1 [6] (See Figure 1). PKA
may also negatively regulate ERKs by the activation of PTPases. Mechanisms for the
activation of ERKs by cAMP are even more varied, usually including Rap1 or Ras, and
even cAMP directly.[6]
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.
Transmembrane Crosstalk[edit source | editbeta]
Crosstalk can even be observed across membranes. Membrane interactions with the
extracellular matrix (ECM) and with neighboring cells can trigger a variety of responses
within the cell. 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] Binding of the α5β1 integrin
to its ligand (fibronectin) activates the formation of fibrillar adhesions and actin
filaments.[5] Yet, if the ECM is immobilized, matrix reorganization of this kind and
formation of fibrillar adhesions is inhibited.[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.[7] (See Figure 2)
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.
Crosstalk in Lymphocyte Activation[edit source |
editbeta]
A more complex, specific example of crosstalk between two major signaling pathways
can be observed with the interaction of the cAMP and MAPK signaling pathways in the
activation of lymphocytes. In this case, components of the cAMP pathway directly and
indirectly affect MAPK signaling pathway meant to activate genes involving immunity
and lymphocytes.
Newly-formed cAMP is released from the membrane and diffuses across the intracellular
space where it serves to activate PKA. The catalytic subunit of PKA must bind four
molecules of cAMP to be activated, whereupon activation consists of cleavage between
the regulatory and catalytic subunits.[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 immunosupression
agents.[8] In this case, cAMP serves to inhibit immunity players. PKA type I colocalizes
with the T-cell and B-cell antigen receptors[9] and causes inhibition of T- and B-cell
activation. PKA has even been highlighted as a direct inducer of genes contributing to
immunosupression.[10]
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.[11] 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).,[11][12] The highly-specific binding of Erk and p38 to this subunit
of HePTP results in rapid inactivation of the signaling cascade. (See Figure 3)
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.
Yet, since both HePTP and Erk are cytosolic enzymes,[13] 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.[11] Importantly though, a third phosphorylation site in the noncatalytic N terminus (the KIM region) of HePTP has been found—one that is
phosphorylated to a much higher stoichiometry by the cAMP pathway,[1] in yet another
instance of crosstalk between the cAMP and MAPK pathways.
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. The
MAPK pathway, through Ras, Raf, Mek, and Erk, shows low activity in the presence of
unphosphorylated (active) HePTP. However, activation the cAMP pathway stimulates the
activation of PKA, which in turn phosphorylates HePTP at Ser23. This prevents HePTP
from binding to Erk and frees the MAPK pathway from inhibition, allowing downstream
signaling to continue. (See Figure 4)
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.
Moreover, studies involving smooth muscle cells from the atrium of the heart have shown
that PKA can reduce the activation of MAP kinases in response to platelet-derived
growth factor (PDGF) by phosphorylating the kinase c-Raf.[14] 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.
Works Cited[edit source | editbeta]
1. ^ a b Saxena, M. (1999), "Crosstalk between cAMP-dependent kinase and MAP kinase
through a protein tyrosine phosphatase", Nat. Cell Biol.: 305–311.
2. ^ Scott, J. D. (1991), "Cyclic nucleotide-dependent protein kinases", Pharmacol. Ther.
50 (1): 123–145., doi:10.1016/0163-7258(91)90075-W, PMID 1653962
3. ^ Krupinski J. et al. (1989), "Adenylyl cyclase amino acid sequence: Possible channel- or
transporter-like structure", Science. 244 (4912): 1558–1564.,
doi:10.1126/science.2472670, PMID 2472670
4. ^ a b c Wine, Jeffrey. (1999–2008), "Across the Membrane; Intracellular Messengers:
cAMP and cGMP", Stanford University, PSYCH121.
5. ^ a b c d Katz et al. (2000), "Physical state of the extracellular matrix regulates the
structure and molecular composition of cell–matrix adhesions", Mol. Biol. Cell. 11 (3):
1047–1060., PMC 14830
6. ^ a b c d Philip J.S. Stork & John M. Schmitt. (2002), "Crosstalk between cAMP and MAP
kinase signaling in the regulation of cell proliferation", Trends in Cell Biology. 12 (6):
258–266., doi:10.1016/S0962-8924(02)02294-8, PMID 12074885
7. ^ a b c d e Geiger, B. et al. (2001), "Physical state of the extracellular matrix regulates the
structure and molecular composition of cell–matrix adhesions", Nature Reviews
Molecular Cell Biology. 2 (11): 793–805., doi:10.1038/35099066, PMID 11715046
8. ^ Ledbetter et al. (1986), "Antibody binding to CD5 (Tp67) and Tp44 T cell surface
molecules: effects on cyclic nucleotides, cytoplasmic free calcium, and cAMP-mediated
suppression", J. Immunology 137: 3299–3305.
9. ^ Levy et al. (1996), "Cyclic AMP-dependent protein kinase (cAK) in human B cells: colocalization of type I cAK (RIα2C2) with the antigen receptor during antiimmunoglobulin-induced B cell activation", Eur. J. Immunol. 26 (6): 1290–1296,
doi:10.1002/eji.1830260617, PMID 8647207
10. ^ Whisler et al. (1991), "Cyclic AMP modulation of human B cell proliferative responses:
role of cAMP-dependent protein kinases in enhancing B cell responses to phorboldiesters
and ionomycin", Cell. Immunol. 142 (2): 398–415.
11. ^ a b c Saxena, M. et al. (1999), "Inhibition of T cell signaling by MAP kinase-targeted
hematopoietic tyrosine phosphatase (HePTP)", J. Biol. Chem.
12. ^ Pulido, R. (1998), "PTP-SL and STEP protein tyrosine phosphatases regulate the
activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association
through a kinase interaction motif", EMBO J. 17 (24): 7337–7350.,
doi:10.1093/emboj/17.24.7337, PMC 1171079, PMID 9857190
13. ^ Cobb et al. (1994), "Regulation of the MAP kinase cascade", Cell. Mol. Biol. Res. 40
(3): 253–256., PMID 7874203
14. ^ Graves et al. (1993), "Protein kinase A antagonizes platelet-derived growth factorinduced signaling by mitogen-activated protein kinase in human arterial smooth muscle
cells", Proc. Natl Acad. Sci. USA. 90 (21): 10300–10304., doi:10.1073/pnas.90.21.10300,
PMC 47762, PMID 7694289