Tissue inhibitor of metalloproteinase-1 promotes cell proliferation through YAP/TAZ activation in cancer

Abstract

Tissue inhibitor of metalloproteinase-1 (TIMP-1), a member of the TIMP family (TIMP-1 to 4), is highly expressed in various types of cancer and forms a complex with its receptor CD63 and Integrin β1. However, the precise oncogenic mechanism of TIMP-1 remains unclear. Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) are transcription co-activators enhancing the transcription of specific genes related to cell proliferation. But the mechanism of aberrant YAP/TAZ activation in cancer is not fully understood. Here, we showed that TIMP-1 activates YAP/TAZ as novel downstream targets to promote cell proliferation. The TIMP-1-CD63-Integrin β1 axis activates Src and promotes RhoA-mediated F-actin assembly, leading to LATS1/2 inactivation. This results in under-phosphorylation, protein stabilization and nuclear translocation of YAP/TAZ (YAP/TAZ activation); CTGF production; and cell proliferation. Furthermore, the TIMP-1-YAP/TAZ axis is aberrantly activated in various types of cancer cells or tissues. TIMP-1 knockdown inhibits cell proliferation through YAP/TAZ inactivation in cancer cells. This study found that TIMP-1 accelerates cell proliferation through YAP/TAZ activation in cancer, and suggests the TIMP-1-YAP/TAZ axis may be a novel potential drug target for cancer patients.

TIMP-1 promotes hypermigration of Toxoplasma-infected primary dendritic cells via CD63–ITGB1–FAK signaling

“…Upon ITGB1 activation, FAK auto-phosphorylates Tyr-397 and recruits the kinases SRC and PI3K (Ando et al, 2018;Toricelli et al, 2013). Because FAK is a central node in the ITGB1 signaling cascade, we hypothesized that FAK, and substrate kinases SRC and PI3K, impacted on hypermotility.…”

“…Gene silencing of Timp-1 (shTIMP-1), Cd63 (shCD63) and Itgb1 (shITGB1) and Ab blockade of ITGB1 (Ha2/5 and HMβ1-1) inhibits hypermotility while recombinant mouse TIMP-1 (rmTIMP-1) rescues hypermotility of shTIMP-1-silenced T. gondii-infected DCs. (V) Activated ITGB1 induces FAK Tyr-397 auto-phosphorylation, which in turn activates SRC and PI3K signaling (Ando et al, 2018;Toricelli et al, 2013). FAK and SRC are phosphorylated shortly after challenge with T. gondii.…”

“…Upon binding TIMP-1, CD63 activates the β1-subunit of integrins (ITGB1) (Jung et al, 2006;Lee et al, 2014). In normal and cancer cells, activated ITGB1 recruits focal adhesion kinase (FAK), which auto-phosphorylates Tyr-397 and subsequently recruits SRC kinase (Ando et al, 2018) and phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) (Toricelli et al, 2013), leading to MAPK activation and cytoskeletal rearrangements (Jung et al, 2006;Ando et al, 2018). Mounting evidence suggests TIMP-1-CD63 signaling functions as a key regulator of cancer cell survival (Jung et al, 2006), metastasis (Forte et al, 2017) and stem cell migration (Wilk et al, 2013;Lee et al, 2014).…”

TFF1 antagonizes TIMP‐1 mediated proliferative functions in gastric cancer

“…TIMP1 has been identified as an oncogenic MMP‐independent regulator of cell proliferation and apoptosis in various cell types . In an attempt to define the functional contribution of TIMP1 overexpression in gastric cancer, we have employed in vitro cell models to detect the effect of the TIMP1 inhibition on cellular proliferation.…”

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

“…Several studies have demonstrated that Src can promote YAP/TAZ activity through multiple independent mechanisms ( Figure 2 ) [ 85 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 ]. Src and other Src family kinases (SFKs) can directly phosphorylate YAP [ 85 , 251 , 253 , 255 , 256 , 261 ] and TAZ [ 257 ] to promote their protein stability and activity.…”