Protein kinase clk/STY is differentially regulated during erythroleukemia cell differentiation: a bias toward the skipped splice variant characterizes postcommitment stages

Abstract

Clk/STY is a LAMMER protein kinase capable to phosphorylate serine/arginine-rich (SR) proteins that modulate premRNA splicing. Clk/STY alternative splicing generates transcripts encoding a full-length kinase and a truncated catalytically inactive protein. Here we showed that clk/STY, as well as other members of the family (e.g. clk2, clk3 and clk4), are up-regulated during HMBA-induced erythroleukemia cell differentiation. mRNAs coding for the full-length and the truncated forms were responsible for the overall increased expression. In clk/STY, however, a switch was observed for the ratio of the two alternative spliced products. In undifferentiated cells the full-length transcript was more abundant whereas the transcript encoding for the truncated form predominated at latter stages of differentiation. Surprisingly, overexpression of clk/STY did not alter the splicing switch upon differentiation in MEL cells. These results suggest that clk/STY might contribute to control erythroid differentiation by a mechanism that implicates a balance between these two isoforms.

Clk/STY (cdc2-Like Kinase 1) and Akt Regulate Alternative Splicing and Adipogenesis in 3T3-L1 Pre-Adipocytes

“…After terminal differentiation, the truncated form of Clk1 exceeded the full length on day 8 (Figure 1). Clk1 is alternatively spliced during differentiation of erythroleukemia cells [18]. 3T3-L1 cells showed a similar pattern in switching to the shorter truncated form after terminal differentiation.…”

DNA Replication Fading As Proliferating Cells Advance in Their Commitment to Terminal Differentiation

“…Down regulation of genes characteristic of proliferating cells, including several oncogenes such as myc, myb and PU.1, goes along with cell cycle arrest1314. Concomitantly, expression of a number of differentiated cell-gene markers leads to reactivation of the erythroid differentiation program15161718.…”

Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements

“…Notably, SR proteins are also regulated by Clk kinases, which themselves have PTC 1 splice forms. Modulation of SR proteins with a network of unproductive splicing might affect a wide range of downstream splicing targets [15][16][17] . The association between unproductive splicing and ultraconserved regions extends beyond the SR family to other RNA-binding proteins.…”