The CATS (FAM64A) protein is a substrate of the Kinase Interacting Stathmin (KIS)

Abstract

The CATS protein (also known as FAM64A and RCS1) was first identified as a novel CALM (PICALM) interactor that influences the subcellular localization of the leukemogenic fusion protein CALM/AF10. CATS is highly expressed in cancer cell lines in a cell cycle dependent manner and is induced by mitogens. CATS is considered a marker for proliferation, known to control the metaphase-to-anaphase transition during the cell division. Using CATS as a bait in a yeast two-hybrid screen we identified the Kinase Interacting Stathmin (KIS or UHMK1) protein as a CATS interacting partner. The interaction between CATS and KIS was confirmed by GST pull-down, co-immunoprecipitation and co-localization experiments. Using kinase assay we showed that CATS is a substrate of KIS and mapped the phosphorylation site to CATS serine 131 (S131). Protein expression analysis revealed that KIS levels changed in a cell cycle-dependent manner and in the opposite direction to CATS levels. In a reporter gene assay KIS was able to enhance the transcriptional repressor activity of CATS, independent of CATS phophorylation at S131. Moreover, we showed that CATS and KIS antagonize the transactivation capacity of CALM/AF10.In summary, our results show that CATS interacts with and is a substrate for KIS, suggesting that KIS regulates CATS function.

CATS (FAM64A) abnormal expression reduces clonogenicity of hematopoietic cells

“…The findings that expression of CATS (FAM64A) markedly increased the nuclear localization of CALM/AF10 [19] and that the murine Cats (Fam64A) transcripts were up-regulated in hematopoietic cells (B220 + lymphoid cells) transformed by CALM/AF10 in comparison to the same subpopulation from non-leukemic mice [10, 23], suggested that CATS (FAM64A) may play a role in CALM/AF10-mediated transformation. In agreement with that, CATS (FAM64A) functions as a transcriptional repressor [19] capable of antagonizing the transactivation activity of the leukemic fusion protein CALM/AF10 in a GAL4-based transactivation assay [24]. However, whether CATS (FAM64A) contributes to leukemogenesis remains to be determined.…”

Integrated analysis of expression profiling data identifies three genes in correlation with poor prognosis of triple-negative breast cancer

“…According to its primary functions in mitosis (27), we speculate that CENPA influences survival in cancer by promoting chromosomal segregation, kinetochore association and genomic instability (28). FAM64A is a relatively new molecule, only a few reports exist on its involvement with ovarian cancer cell cycle and proliferation (29), therefore specific mechanisms and pathways on this molecule merit investigation. As for BUB1 and CCNB2, though the relationships with breast cancer has been reported (30,31), their role in TNBC still needs to be further addressed.…”

“…FAM64A is the substrate of the kinase-interacting stathmin (KIS or UHMK1), a serine/threonine protein kinase that promotes cell cycle progression through G1 by phosphorylation of the cyclin-dependent kinase inhibitor 1B (p27 Kip1 ) (29). Since AURKB and BUB1 are also serine/ threonine kinases, we doubt whether FAM64A is a substrate of AURKB or BUB1.…”

The U2AF homology motif kinase 1 (UHMK1) is upregulated upon hematopoietic cell differentiation

“…We suggested a possible role of UHMK1-PIMREG interaction in PICALM/MTT10 mediated leukemogenesis [7].…”

“…Since then it has been described to interact with a range of proteins, such as peptidylglycine α -amidating monooxygenase (PAM) [2]; cyclin dependent kinase inhibitor (CDKI) p27 KIP1 [3]; splicing factors SF1 [4] and SF3b155 [5]; components of the neuronal RNA granules NonO, KIF3A and eEF1A [6]; proliferation marker PIMREG [7]; and RNA-binding proteins CPEB1, CPEB2 and CPEB3 [8], shedding light on different functions of UHMK1 in diverse cellular processes.…”