Regulation of lymphocyte fate by Ras/ERK signals

Abstract

The Ras-ERK cascade is activated by countless external cues that stimulate diverse receptors. Therefore, the mechanisms by which distinct receptors dictate different cellular outcomes by activating the same signaling module has long fascinated many researchers. Initial clues came from observations that the duration of ERK activation is critical to cell-fate decisions. In classical experiments, PC12 cells proliferated after transient ERK activation by epidermal growth factor, but terminally differentiated after more sustained ERK activation by nerve growth factor. Subsequent studies suggested that the duration of ERK signaling is interpreted by cells through a network of immediate-early genes. Nevertheless, it remains ill-defined how the duration and strength of Ras-ERK signaling is established and what genes are differently regulated, thereby translating the response into different biological outcomes. Recent studies with lymphocytes have evoked a new idea that two types of interconnected mechanisms can contribute to the sensitivity and robustness of the ERK activity; (1) interplay between two types of Ras activators (Sos and RasGRP); (2) existence of two subcellular compartments for Ras activation (plasma membrane and Golgi). Moreover, candidate immediate early genes that regulate lymphocyte proliferation and differentiation have emerged.

MAP Kinase Cascades in Antigen Receptor Signaling and Physiology

“…Moreover, introduction of exogenous μH into Rag-deficient pro-B cells resulted in the formation of surface pre-BCR (Kawano, Yoshikawa, Minegishi, & Karasuyama, 2006), which is associated with an increased phosphorylation level of ERK and initiation of pro-B cell division. MEK inhibitor U0126 treatment completely abrogated ERK phosphorylation as well as cell proliferation of μH-introduced Rag-deficient pro-B cells, indicating ERK is a direct target of pre-BCR signaling and MEK is the only upstream MAPKK for ERK activation in the pre-BCR signaling pathway associated with cell proliferation (Yasuda et al, 2008) (Yasuda et al, 2008) (Fig. 2).…”

“…The signaling pathway leading from Ras to ERK is initiated by the BCR and pre-BCR, and this is critical for a number of B cell functions and fate decisions (Hendriks & Middendorp, 2004;Kurosaki, Shinohara, & Baba, 2010;Milne, Fleming, Zhang, & Paige, 2004;Reth & Nielsen, 2014;Yasuda & Kurosaki, 2008). Crosslinking of Igβ, a signaling subunit of both pre-BCR and BCR, using monoclonal antibody recognizing extracellular portion of Igβ, predominantly induces activation of ERK (Nagata et al, 1997).…”

“…Therefore, disruption of the proximal pre-BCR signaling components such as IgH (Kitamura, Roes, Kuhn, & Rajewsky, 1991), λ5 surrogate light chain (Kitamura et al, 1992), cytoplasmic region of Igα/Igβ signaling subunits (Reichlin et al, 2001;Kraus et al, 2001), Syk/Zap-70 tyrosine kinases 9 (Schweighoffer, Vanes, Mathiot, Nakamura, & Tybulewicz, 2003;Turner et al, 1995;Yasuda et al, 2008), and Blk/Fyn/Lyn Src-family tyrosine kinases (SFKs) (Saijo et al, 2003) arrests development at this stage. The Syk/Zap-70-dependent pathway and SFK-dependent pathways are crucial for pre-B cell development through NF-κB-independent and -dependent mechanisms, respectively (Saijo et al, 2003;Schweighoffer et al, 2003).…”

“…Conditional deletion of ERK2 together with germline deletion of ERK1 is associated with defective pre-BCR-mediated cell cycling, as well as a complete block in the transition from the pro-B to the pre-B cell stage (Yasuda et al, 2008).…”

“…In fact, ERK-deficient pro-B cells are more susceptible to cell death than wild-type pro-B cells and expression of the prosurvival gene Bcl2 is induced by anti-Igβ stimulation of μMT pro-B cells in an ERK-dependent manner (Yasuda et al, 2008). The ERK signaling pathway is also involved in post-transcriptional regulation of the proapoptotic proteins, Bim and c-Myc, by phosphorylation and subsequent degradation, thereby contributing to cell survival (Craxton, Draves, Gruppi, & Clark, 2005;Sears et al, 2000).…”