Interest is great in the new molecular concepts that explain, at the
level of signal transduction, the process of reprogramming. Usually,
transcription factors with developmental importance are used, but these
approaches give limited information on the signaling networks involved,
which could reveal new therapeutic opportunities. Recent findings
involving reprogramming by genetic means and soluble factors with
well-studied downstream signaling mechanisms, including signal
transducer and activator of transcription 3 (STAT3) and hairy and
enhancer of split 3 (Hes3), shed new light into the molecular mechanisms
that might be involved. We examine the appropriateness of common culture
systems and their ability to reveal unusual (noncanonical) signal
transduction pathways that actually operate in vivo. We then discuss
such novel pathways and their importance in various plastic cell types,
culminating in their emerging roles in reprogramming mechanisms. We also
discuss a number of reprogramming paradigms (mouse induced pluripotent
stem cells, direct conversion to neural stem cells, and in vivo
conversion of acinar cells to beta-like cells). Specifically for
acinar-to-beta-cell reprogramming paradigms, we discuss the common view
of the underlying mechanism (involving the Janus kinase-STAT pathway
that leads to STAT3-tyrosine phosphorylation) and present alternative
interpretations that implicate STAT3-serine phosphorylation alone or
serine and tyrosine phosphorylation occurring in sequential order. The
implications for drug design and therapy are important given that
different phosphorylation sites on STAT3 intercept different signaling
pathways. We introduce a new molecular perspective in the field of
reprogramming with broad implications in basic, biotechnological, and
translational research