Keratin binding to 14-3-3 proteins modulates keratin filaments and hepatocyte mitotic progression

Abstract

Keratin polypeptides 8 and 18 (K8͞18) are the major intermediate filament proteins of simple-type epithelia. K18 Ser-33 phosphorylation regulates its binding to 14-3-3 proteins during mitosis. We studied the significance of keratin binding to 14-3-3 in transgenic mice that overexpress wild-type or Ser-333 Ala (S33A) K18. In S33A but not wild-type K18-overexpressing mice, pancreatic acinar cell keratin filaments retracted from the basal nuclear region and became apically concentrated. In contrast, K18 S33A had a minimal effect on hepatocyte keratin filament organization. Partial hepatectomy of K18-S33A-overexpressing mice did not affect liver regeneration but caused limited mitotic arrest, accumulation of abnormal mitotic figures, dramatic fragmentation of hepatocyte keratin filaments, with retention of a speckled 14-3-3 mitotic cell nuclear-staining pattern that usually becomes diffuse during mitosis. Hence, K18 Ser-33 phosphorylation regulates keratin filament organization in simple-type epithelia in vivo. Keratin binding to 14-3-3 may partially modulate hepatocyte mitotic progression, in association with nuclear redistribution of 14-3-3 proteins during mitosis.mitosis ͉ phosphorylation ͉ pancreas ͉ liver

Type of Article: Original Article Role of Cytokeratin Biomarkers in Breast Carcinoma

“…CK also plays promising role in vaccination trial and in understanding cellular processes such as apoptosis, mitosis, cell cycle progression, and cell signaling, etc. [7][8][9][10][11]. The aim of this study was to analyze the CK5, 14, and 8/18 markers in breast tissue and to determine the correlation between hormone receptor status (ER, PR, and Her2/neu) along with clinic-pathological factors.…”

Reg-II Is an Exocrine Pancreas Injury-Response Product That Is Up-Regulated by Keratin Absence or Mutation

“…The K18 S52A mutation does not affect keratin filament organization in the pancreas (or the liver) under basal conditions, whereas the K18 S33A mutation maintains acinar cell cytoplasmic filaments, although they become retracted toward the apical pole (Ku et al, 2002). These findings suggest that a signaling event that involves K18 Ser52 is likely to be important in modulating downstream up-regulation of Reg-II expression.…”

“…Based on available data, K18 S33 and S52 phosphorylation have different cell response behaviors and functions. S33 phosphorylation mediates K18 binding with 14-3-3 proteins, and S33 phosphorylation decreases during apoptosis (Ku et al, 2002(Ku et al, , 2003. In contrast, K18 S52 phosphorylation increases during apoptosis (Ku et al, 2003), and its mutation predisposes mice to hepatotoxic injury but the role of these two phosphorylation sites in pancreatic injury has not been studied.…”

“…Schematic acinar cells highlight the phenotype of the keratin filament network in K8-WT and K8-null mice by displaying cytoplasmic filaments and apicolateral membraneproximal filaments (N, nucleus; large dots, zymogen granules). K18 S33A mice ( Figure 5C), which exhibit a retraction of the keratin cytoplasmic filaments from the basal supranuclear compartment toward the apical domain (Ku et al, 2002). In contrast, blocking K18 S52 phosphorylation results in elevated Reg-II protein levels in two of four tested mice for each genotype ( Figure 5D).…”

“…We used K8, K18, or K19 null mice and transgenic mouse lines that overexpress wild-type (WT) human (h) K18 or K18 R89C , K18 S33A (Ku et al, 2002), or K18 S52A . For the K18 S33A and S52A mice, two independent mouse lines for each mutation were used (S33A 1 and S33A 2 ; S52A 1 and S52A 2 ).…”