Functional analysis of LATS protein kinases, products of novel tumor-suppressor genes

LATS1和LATS2基因是果蝇LATS（大肿瘤抑制基因）的哺乳动物同源基因，该基因编码丝氨酸/苏氨酸激酶。虽然LATS2在各种人类癌细胞系中表达，但我们发现一些肾肿瘤细胞系不表达LATS2。LATS1和Bcl-2在lats2阳性细胞中高度磷酸化，而在lats2缺失的紫杉醇处理细胞中不磷酸化。此外，lats2缺陷细胞对紫杉醇诱导的凋亡不太敏感。在LATS2缺陷细胞中，异位表达LATS2可恢复紫杉醇敏感性，导致LATS1和Bcl-2磷酸化，并诱导细胞凋亡。这些观察结果表明，LATS2通过控制LATS1和Bcl-2磷酸化参与m期进展，从而调节细胞进入凋亡，并提示临床肿瘤中LATS激酶基因的状态可能决定了它们对紫杉醇介导的化疗的敏感性。

The LATS1 and LATS2 genes are mammalian homologs of the Drosophila LATS (large tumor suppressor) gene that encodes a serine/threonine kinase. Although LATS2 is expressed in various human cancer cell lines, we identified some kidney tumor cell lines that do not express LATS2. Both LATS1 and Bcl-2 are highly phosphorylated in LATS2-positive but not in LATS2-deficient, paclitaxel-treated cells.In addition, LATS2-deficient cells are less sensitive to paclitaxel-induced apoptosis. Ectopic expression of LATS2 in LATS2-deficient cells restores paclitaxel sensitivity , resulting in the phosphorylation of LATS1 and Bcl-2, and the induction of apoptosis. These observations indicate that LATS2 is involved in M-phase progression through the control of LATS1 and Bcl-2 phosphorylation, thereby regulating cellular entry into apoptosis and suggest that the status of LATS kinase genes in clinical tumors may define their sensitivity to paclitaxel-mediated chemotherapy.