The origin of GSKIP, a multifaceted regulatory factor in the mammalian Wnt pathway.

GSK3ß interacting protein (GSKIP) is a naturally occurring negative regulator of GSK3ß and retains both the Protein Kinase A Regulatory subunit binding (PKA-RII) domain and GSK3ß interacting domain. Of these two domains, we found that PKA-RII is required for forming a working complex comprising PKA/GSKIP/GSK3ß/Drp1 to influence phosphorylation of Drp1 Ser637. In this study, bioinformatics and experimental explorations re-analyzing GSKIP's biofunctions suggest that the evolutionarily conserved Domain of Unknown Function (DUF727) is an ancestral prototype of GSKIP in prokaryotes, and acquired the C-terminal GSK3ß binding site (tail) in invertebrates except for Saccharomyces spp., after which the N-terminal PKA-RII binding region (head) evolved in vertebrates. These two regions mutually influence each other and modulate GSKIP binding to GSK3ß in yeast two-hybrid assays and co-immunoprecipitation. Molecular modeling showed that mammalian GSKIP could form a dimer through the L130 residue (GSK3ß binding site) rather than V41/L45 residues. In contrast, V41/L45P mutant facilitated a gain-of-function effect on GSKIP dimerization, further influencing binding behavior to GSK3ß compared to GSKIP wild-type (wt). The V41/L45 residues are not only responsible for PKA RII binding that controls GSK3ß activity, but also affect dimerization of GSKIP monomer, with net results of gain-of-function in GSKIP-GSK3ß interaction. In addition to its reported role in modulating Drp1, Ser637 phosphorylation caused mitochondrial elongation; we postulated that GSKIP might be involved in the Wnt signaling pathway as a scavenger to recruit GSK3ß away from the ß-catenin destruction complex and as a competitor to compete for GSK3ß binding, resulting in accumulation of S675 phosphorylated ß-catenin.

A clinicopathologic and molecular study of follicular lymphoma in Taiwan.

BACKGROUND: The clinicopathologic and molecular features of follicular lymphoma (FL) in Taiwan have not been well defined. We conducted a retrospective study including history review, immunohistochemistry, and molecular study for the major breakpoint region (MBR) of t(14;18) and correlated these findings with survival. PATIENTS AND METHODS: Sixty-five FLs were identified, with a male to female ratio of 1.9:1 and a median age of 63 years (mean, 60 years). Sixty cases (92%) were nodal, 4 (6%) were extranodal, and 1 (2%) was indeterminate. The median ages of the nodal and extranodal cases were 63 years and 44 years, respectively. Disease staging in 59 patients included 15 patients (25%) with stage I disease, 14 (24%) with stage II, 20 (34%) with stage III, and 10 (17%) with stage IV. Forty-four patients received chemotherapy, 2 patients received chemotherapy with palliative radiation therapy, and 13 patients received supportive treatment/observation. RESULTS: The 5-year survival rate was 52.6%. The cases were classified as grades 1 (n = 27; 42%), 2 (n = 22; 34%), 3A (n = 13; 20%), and 3B (n = 3; 5%). Twenty cases (31%) were positive for MBR, including 19 of 57 (33%) nodal cases and 1 of 4 (25%) primary extanodal FLs. Patients with low-stage disease (stages I/II) had a better survival rate than patients with high-stage disease (III/IV; log-rank test, P = 0.012). CONCLUSION: This is the largest series of Taiwanese FLs with immunophenotypes and MBR detection rates similar to those of the West. Disease stage was statistically significant with regard to survival. Although the number of extranodal FLs cases was small, the patients were younger, their tumors had lower CD10 expression, and they had more favorable survival rates than patients with nodal disease.