Abstract
The non-receptor tyrosine kinase LCK belongs to the SRC family of kinases. SRC family kinases are proto-oncogenes that have long been known to play key roles in cell proliferation, motility, morphology and survival. Here we show that LCK regulates the function of the type III receptor tyrosine kinase FLT3 in murine pro-B cells. We observed that expression of LCK significantly enhances the colony forming capacity of the constitutively active FLT3 mutant FLT3-ITD (internal tandem duplication). Furthermore, cells expressing LCK developed tumor earlier compared to cells transfected with empty control vector. Staining of the tissues from mouse xenografts showed higher Ki67 staining in cells expressing LCK suggesting that expression of LCK enhances the FLT3-ITD-mediated proliferative capacity. LCK expression did not affect either FLT3-WT or FLT3-ITD -induced AKT, ERK1/2 or p38 phosphorylation. However, LCK expression significantly enhanced FLT3-ITD-mediated STAT5 phosphorylation. Taken together, our data suggest that LCK cooperates with oncogenic FLT3-ITD in cellular transformation.
Highlights
Cells with hyperphosphorylated FLT3 display high levels of LCK phosphorylation[29] suggesting a possible role of FLT3 in LCK activation or vice versa
It is long been known that SRC family kinases (SFKs) play important roles in mitogenic signaling
SFKs act as an intermediate mediator of various receptor tyrosine kinases
Summary
Cells with hyperphosphorylated FLT3 display high levels of LCK phosphorylation[29] suggesting a possible role of FLT3 in LCK activation or vice versa. Apart from cells of hematopoietic origin, LCK is aberrantly expressed in a number of other cancer types, including breast cancer, colon cancer and small cell lung carcinoma[30,31,32] suggesting that it has general cancer promoting activities. Several studies have reported high levels of LCK expression in acute myeloid leukemia. Studies indicated high expression of LCK in leukemic cells from patients with less differentiated AML, i. In this report we show, using the proB cell line Ba/F3 that lacks endogenous LCK, that LCK expression is not essential for wild-type FLT3 signaling but plays an important role in oncogenic FLT3-ITD-mediated cellular transformation
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