Signaling Pathways for PC12 Cell Differentiation: Making the Right Connections

Abstract

A key issue in signal transduction is how signaling pathways common to many systems-so-called canonical signaling cassettes-integrate signals from molecules having a wide spectrum of activities, such as hormones and neurotrophins, to deliver distinct biological outcomes. The neuroendocrine cell line PC12, derived from rat pheochromocytoma, provides an example of how one canonical signaling cassette-the Raf --> mitogen-activated protein kinase kinase (MEK) --> extracellular signal-regulated kinase (ERK) pathway-can promote distinct outcomes, which in this case include neuritogenesis, gene induction, and proliferation. Two growth hormones, epidermal growth factor (EGF) and nerve growth factor (NGF), use the same pathway to cause PC12 proliferation and differentiation, respectively. In addition, pituitary adenylate cyclase-activating polypeptide (PACAP), a neurotransmitter that also causes differentiation, uses the same canonical cassette as NGF but in a different way. The Connections Map for PC12 Cell Differentiation brings into focus the complex array of specific cellular responses that rely on canonical signal transduction systems.

Sur8/Shoc2 Involves Both Inhibition of Differentiation and Maintenance of Self-Renewal of Neural Progenitor Cells via Modulation of Extracellular Signal-Regulated Kinase Signaling

“…It is known that the Ras-ERK pathway plays a role in both inhibition of differentiation and activation of proliferation [11,34,35]. The Ras-ERK pathway differentially regulates differentiation and proliferation of cells according to the intensity and duration of the signal [36][37][38][39][40][41][42]. The importance of the kinetics of ERK activation in the determination of neuronal cell fate is dependent on the physiological status of Ras-ERK pathway activation [43][44][45].…”

Targeting SMN to Cajal bodies and nuclear gems during neuritogenesis

“…The rat pheochromocytoma cell line, PC12, is a useful model system for studying many cellsignaling pathways, especially those leading to neuritogenesis, a cellular hallmark of neuronal differentiation (Vaudry et al 2002). The current view is that differentiation is produced not by induction of entirely novel signaling pathways for a given cell fate, but rather from unique combinations of canonical signaling cassettes.…”

“Soluble” adenylyl cyclase‐generated cyclic adenosine monophosphate promotes fast migration in PC12 cells

“…The rat pheochromocytoma cell line PC12 has been extensively used as a model for the morphological changes that accompany both processes. When treated with nerve growth factor (NGF) for long periods (48-72 hr), PC12 cells extend neurites in a process analogous to differentiation of sympathetic neurons (Levi-Montalcini and Angeletti, 1968;Greene and Tischler, 1982;Vaudry et al, 2002). Conversely, when PC12 cells, plated on laminin-coated surfaces, are simultaneously stimulated with NGF and phorbol 12-myristate-13-acetate (PMA), the cell body recedes away from points of attachment to the plate surface, and the cells assume a crescent shape (Glowacka and Wagner, 1990).…”

“…Specifically, it is known that PMA exerts its effects via the activation of protein kinase C (PKC), which was independently shown to be essential for cell motility in primary (Choe et al, 2003). NGF has been shown to promote the survival and differentiation of multiple neuronal populations within the central nervous system (LeviMontalcini and Angeletti, 1968), but the signaling mechanisms involved in NGF-induced neuritogenesis remain controversial (Vaudry et al, 2002).We recently identified "soluble" adenylyl cyclase (sAC) as the source of cAMP downstream of NGF and a mediator of NGF-induced activation of the monomeric GTPase Rap1 in PC12 cells (Stessin et al, 2006). sAC is a ubiquitously expressed cAMP source in mammalian cells, distinct from the classically described trans-membrane adenylyl cyclases (tmACs) in its subcellular localization and biochemical profile.…”

“…NGF has been shown to promote the survival and differentiation of multiple neuronal populations within the central nervous system (LeviMontalcini and Angeletti, 1968), but the signaling mechanisms involved in NGF-induced neuritogenesis remain controversial (Vaudry et al, 2002).…”