Abstract
When properly employed, targeted therapies are effective cancer treatments. However, the development of such therapies requires the identification of targetable drivers of cancer development and metastasis. The expression and nuclear localization of the transcriptional coactivators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are increased in many human cancers, and experimental evidence indicates that aberrant YAP or TAZ activation drives tumor formation and metastasis. Although these findings make YAP and TAZ appealing therapeutic targets, both have important functions in adult tissues, so directly targeting them could cause adverse effects. The identification of pathways active in cancer cells and required for YAP/TAZ activity could provide a way to inhibit YAP and TAZ. Here, we show that SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) is an important driver of YAP/TAZ activity in human breast cancer and melanoma cells. SRC activation increased YAP/TAZ activity and the expression of YAP/TAZ-regulated genes. In contrast, SRC inhibition or knockdown repressed both YAP/TAZ activity and the expression of YAP/TAZ-regulated genes. We also show that SRC increases the activity of YAP and TAZ by repressing large tumor suppressor homolog (LATS), and we identify the GTPase-activating protein GIT ArfGAP 1 (GIT1) as an SRC effector that regulates both YAP and TAZ. Importantly, we demonstrate that SRC-mediated YAP/TAZ activity promotes tumor growth and enhances metastasis and that SRC-dependent tumor progression depends, at least in part, on YAP and TAZ. Our findings suggest that therapies targeting SRC could help manage some YAP/TAZ-dependent cancers.
Highlights
When properly employed, targeted therapies are effective cancer treatments
We show that GTPase-activating protein GIT ArfGAP 1 (GIT1) is an SRC effector that regulates Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) activity in both melanoma and breast cancer cells
It is clear that increased YAP/TAZ activity is prevalent in human cancer, but it remains unclear exactly how YAP and TAZ become activated in most cancer types
Summary
SRC activation promotes YAP/TAZ transcriptional activity and target gene expression. As discussed above, it is clear that increased YAP/TAZ activity is prevalent in human cancer, but it remains unclear exactly how YAP and TAZ become activated in most cancer types. Dasatinib treatment prevented the adhesion-mediated decrease in LATS and YAP phosphorylation (Fig. 5, A and B) and the increase in YAP/TAZ activity and CTGF and CYR61 mRNA expression (Fig. 5, C and D), indicating that these effects are SRC-dependent These results show that activation of endogenous SRC through integrin–ECM adhesion represses LATS activity and promotes YAP/TAZ function. Expression of either activated RhoA or activated RhoC could rescue YAP/TAZ activity in cells treated with dasatinib, but neither was able to reduce the LATS-mediated phosphorylation of YAP (Fig. S4E), suggesting that Rho is promoting YAP/ TAZ activity through a different pathway than SRC. Whereas expression of dominant-negative RhoA or RhoC constructs did reduce YAP/TAZ activity in both control and SRCY527F-expressing cells (Fig. S4F), SRC activation still significantly increased YAP/TAZ activity in cells expressing these dominant-negative Rho constructs (Fig. S4F) These data suggest that another SRC effector pathway that regulates LATS must exist. Our results indicate that SRC-mediated YAP/TAZ activation drives tumor growth and metastasis and suggest that this pathway is a potential therapeutic target
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