Integration of signals from the B-cell antigen receptor and the IL-4 receptor leads to a cooperative shift in the cellular response axis.
Lahesmaa Riitta; Jamal Md. Sarwar; Jarvenpaa Henna; Ravichandran Srikanth; Rao Kanury VS; Aflakian Nooshin
https://urn.fi/URN:NBN:fi-fe2021042717398
Tiivistelmä
Although intracellular signaling events activated through individual
cell surface receptors have been characterized in detail, cells are
often exposed to multiple stimuli simultaneously in physiological
situations. The response elicited then is defined through the
cooperative interactions between signals activated by these multiple
stimuli. Examples of such instances include cooperativity between
individual isoforms of G-protein-coupled receptors, between different
growth factor receptors, or between growth factor and integrin
receptors. Mechanisms by which the integration of signals emanating from
independent receptors influences cellular responses, however, are
unknown. In this report, we studied interactions between the antigen and
the IL-4 receptors in immature B cells. While stimulation through the
B-cell antigen receptor alone causes cell cycle arrest and subsequent
apoptosis, the inclusion of IL-4 during stimulation provides a
protective effect. We therefore sought to obtain a systems view on how
crosstalk between the two respective cell surface receptors modulates
the cellular response. We found that, in comparison to the effects of
B-cell receptor activation alone, combined stimulation through both
receptors enforced a marked reorientation in the 'survival vs.
apoptosis' axis of the signaling machinery. The consequent modulation of
transcription factor activities yielded an integrated network, spanning
the signaling and the transcriptional regulatory components, that was
now biased towards the recruitment of molecules with a pro-survival
function. This alteration in network properties influenced early-induced
gene expression, in a manner that could rationalize the antagonistic
effect of the IL-4 receptor on B-cell receptor signaling. Importantly,
this antagonism was achieved through an expansion in the repertoire of
the genes expressed, wherein the newly generated products counteracted
the effects of the B-cell receptor-specific subset. Thus the plasticity
of the regulatory networks is also experienced at the level of gene
expression, and is the resultant pattern obtained that then modulates
cell-fate decisions.
Kokoelmat
- Rinnakkaistallenteet [19207]