c-Jun N-terminal Kinase Phosphorylation of Stathmin Confers Protection against Cellular Stress

Abstract

The cell stress response encompasses the range of intracellular events required for adaptation to stimuli detrimental to cell survival. Although the c-Jun N-terminal kinase (JNK) is a stressactivated kinase that can promote either cell survival or death in response to detrimental stimuli, the JNK-regulated mechanisms involved in survival are not fully characterized. Here we show that in response to hyperosmotic stress, JNK phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (STMN), on conserved Ser-25 and Ser-38 residues. In in vitro biochemical studies, we identified STMN Ser-38 as the critical residue required for efficient phosphorylation by JNK and identified a novel kinase interaction domain in STMN required for recognition by JNK. We revealed that JNK was required for microtubule stabilization in response to hyperosmotic stress. Importantly, we also demonstrated a novel cytoprotective function for STMN, as the knockdown of STMN levels by siRNA was sufficient to augment viability in response to hyperosmotic stress. Our findings show that JNK targeting of STMN represents a novel stress-activated cytoprotective mechanism involving microtubule network changes.

Growth Cone MKK7 mRNA Targeting Regulates MAP1b-Dependent Microtubule Bundling to Control Neurite Elongation

“…JNKs phosphorylate and regulate mt-associated proteins (MAPs), consequently, JNK1-deficient mice display loss of axonal mt integrity [15]. JNKs phosphorylate the catastrophy promoting factors stathmins [16] and the protein SCG10 [17], which exhibits mt depolymerizing activity. JNKs also phosphorylate doublecortins to modulate neurite outgrowth and neuronal migration [18].…”

WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.

“…Total cell lysates were prepared in RIPA buffer [50 mM Tris-HCl, pH 7.3, 150 mM NaCl, 0.1 mM EDTA, 1% (w/v) sodium deoxycholate, 1% (v/v) Triton X-100, 0.2% (w/v) NaF and 100 mM Na 3 VO 4 ] supplemented with protease inhibitors and immunoblotted as previously described (Ng et al, 2010) with the exception that protein lysates were resolved on SDS-PAGE without sample boiling due to the heat sensitivity of WDR62 (Wasserman et al 2010). For phosphatase treatment, lysates were prepared in RIPA buffer lacking EDTA, NaF and Na 3 VO 4 .…”

Effects of Maternal Marginal Iodine Deficiency on Dendritic Morphology in the Hippocampal CA1 Pyramidal Neurons in Rat Offspring

“…Both MAP2 and stathmin can be phosphorylated by JNK1 and determine dendritic length and arbor complexity (Bjorkblom et al 2005;Ng et al 2010). To further understand the potential etiology for down-regulated phospho-MAP2 and phospho-stathmin in marginal ID and severe ID groups, we analyzed the The levels of FT 4 , TT 4 , FT 3 and TSH in all groups on PN7 (n = 5), PN14 (n = 8), PN21 (n = 10) and PN28 (n = 10) from the pups were measured by supersensitive chemiluminescence immunoassay.…”

“…Stathmin is regarded as a microtubule-destabilizing factor, highly expressed in the developing nervous system (Grenningloh et al 2004). Recently, a novel discovery showed that phosphorylation by JNK1 negatively regulated the microtubule-destabilizing activity of stathmin (Ng et al 2010).…”