Mask Is Required for the Activity of the Hippo Pathway Effector Yki/YAP

Abstract

Summary The Drosophila Yorkie (Yki) protein and its mammalian homolog Yes-associated protein (YAP) are potent growth promoters and YAP overexpression is associated with multiple types of cancer [1,2]. Yki and YAP are transcriptional co-activators and function as downstream effectors of the Hippo tumor suppressor pathway [1–4]. The regulation of Yki and YAP by the Hippo signaling pathway has been extensively investigated, however, how they regulate gene expression is poorly understood. To identify additional regulators of Yki activity we performed a genome-wide RNAi screen in Drosophila S2 cells. In this screen, we identified the conserved protein Mask (Multiple ankyrin repeats single KH domain) as a novel promoter of Yki activity in vitro and validated this function in vivo in Drosophila. We found that Mask is required downstream of the Hippo pathway for Yki to induce target gene expression and that Mask forms complexes with Yki. The human Mask homolog MASK1 complexes with YAP and it is required for full activity of YAP and elevated MASK1 expression is associated with worsened outcomes for breast cancer patients. We conclude that Mask is a novel cofactor for Yki/YAP required for optimal Yki/YAP activity during development and oncogenesis.

Binding partners of the kinase domains inDrosophilaobscurin and their effect on the structure of the flight muscle

“…MASK is a cofactor of Drosophila Yorkie (Yki) and mammalian Yes-associated protein (YAP) in the Hippo signalling pathway, which controls tissue growth. The signalling function in this pathway is similar for Drosophila and human MASK (Sansores-Garcia et al, 2013;Sidor et al, 2013); however, MASK isoforms have not been found it human muscle. There is a sequence in the C. elegans genome that codes for a protein with homology to Drosophila, mouse and human MASK (Smith et al, 2002).…”

“…There are two smaller homologues of MASK in human cells: MASK1 (Ankhd1) and MASK2 (Ankrd17), which have the same domain structure as Drosophila MASK. The Drosophila protein (∼400 kDa) is larger than the human proteins (∼280 kDa), mainly due to a longer stretch of sequence between the ankyrin repeat domains (Sansores-Garcia et al, 2013;Sidor et al, 2013). MASK is a cofactor of Drosophila Yorkie (Yki) and mammalian Yes-associated protein (YAP) in the Hippo signalling pathway, which controls tissue growth.…”

Ankyrin repeat and single KH domain 1 (ANKHD1) drives renal cancer cell proliferation via binding to and altering a subset of miRNAs

“…It was later shown to regulate additional signalling cascades including the cancer-associated HIPPO (11)(12)(13)(14) and PINK/Parkin in Drosophila (15). Clinical epidemiological studies suggested that ANKHD1 is elevated and may be involved in acute leukaemia (16) and prostate cancer (11).…”

ANKHD1 (ankyrin repeat and KH domain containing 1)

“…In humans, ANKHD1 associates with SHP2, however the biologic consequence of this protein interaction remains indeterminate (Traina, et al, 2006). ANKHD1 and YAP1 interaction has also been confirmed in human cells (HEK293 and DU145 cells) and modulates the Hippo signaling pathway activation, proliferation and cell cycle progression (Sidor, et al, 2013, Sansores-Garcia, et al, 2013, Machado-Neto, et al, 2014.…”

“…In two independent cohorts of breast cancer patients, high expression of ANKHD1 was associated with worsened outcomes (Sansores-Garcia, et al, 2013).…”