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Serum Deprivation Inhibits the Transcriptional Co-Activator YAP And Serum deprivation inhibits the transcriptional co-activator YAP and cell growth via phosphorylation of the 130-kDa isoform of Angiomotin by the LATS1/2 protein kinases Jacob J. Adlera, Derrick E. Johnsona, Brigitte L. Hellera, Lauren R. Bringmana, William P. Ranahana, Michael D. Conwellb, Yang Sunb, Andy Hudmona,c, and Clark D. Wellsa,1 aDepartment of Biochemistry and Molecular Biology, bDepartment of Ophthalmology, Glick Eye Institute, and cStark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202 Edited* by Tony Pawson, Samuel Lunenfeld Research Institute, Toronto, ON, Canada, and approved September 17, 2013 (received for review May 3, 2013) Large tumor suppressor (LATS)1/2 protein kinases transmit Hippo all bind and inhibit YAP and TAZ (17–19). Amot associates with signaling in response to intercellular contacts and serum levels to cell junctions and binds apical polarity proteins, which underlie its limit cell growth via the inhibition of Yes-associated protein (YAP). ability to control cell shape and migration (20–23). The 130 kDa Here low serum and high LATS1 activity are found to enhance the isoform of Amot (Amot130), unlike the 80-kDa isoform (Amot80) levels of the 130-kDa isoform of angiomotin (Amot130) through that promotes cell growth (24), binds and inhibits YAP through phosphorylation by LATS1/2 at serine 175, which then forms a cytosolic sequestration (17, 18) and by facilitating its degradation binding site for 14-3-3. Such phosphorylation, in turn, enables the (25) in a manner that can be independent of YAP phosphorylation ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiq- by LATS1/2 at residue Ser-127 (17, 18). uitinate, and stabilize Amot130. Consistently, the Amot130 (S175A) This study finds that Amot130 both induces and transmits Hippo mutant, which lacks LATS phosphorylation, bound AIP4 poorly under signaling in response to serum deprivation in a manner that all conditions and showed reduced stability. Amot130 and AIP4 requires its direct phosphorylation by LATS1/2. This underlies also promoted the ubiquitination and degradation of YAP in re- a process where Amot130 then binds atrophin-1 interacting protein (AIP)4 to promote YAP degradation and consequently sponse to serum starvation, unlike Amot130 (S175A). Moreover, CELL BIOLOGY silencing Amot130 expression blocked LATS1 from inhibiting the to inhibit YAP-dependent transcription and cell growth. expression of connective tissue growth factor, a YAP-regulated Results gene. Concordant with phosphorylated Amot130 specifically me- diating these effects, wild-type Amot130 selectively induced YAP Serum Deprivation and LATS1 Activity Control the Protein Levels of phosphorylation and reduced transcription of connective tissue Amot130. The serum factors sphingosine-1-phosphate (S-1-P) (2, 3) growth factor in an AIP4-dependent manner versus Amot130 and lysophosphatidic acid (LPA) (2) activate YAP through G (S175A). Further, Amot130 but not Amot130 (S175A) strongly protein-coupled receptor-initiated signaling. Here the converse inhibited the growth of MDA-MB-468 breast cancer cells. The process, whereby serum starvation induces Hippo signaling, was dominant-negative effects of Amot130 (S175A) on YAP signaling investigated in breast cancer and nontransformed model cell also support that phosphorylated Amot130 transduces Hippo sig- lines. Initially, the effects of serum starvation were measured on naling. Likewise, Amot130 expression provoked premature growth the Hippo pathway proteins Amot130, AmotL1, LATS1, YAP, and TAZ by immunoblot. The phosphorylation of LATS1 at arrest during mammary cell acini formation, whereas Amot130 fi (S175A)-expressing cells formed enlarged and poorly differentiated Ser-909, a surrogate measure of activity, increased signi cantly acini. Taken together, the phosphorylation of Amot130 by LATS is by 24 h, whereas the levels of YAP and TAZ declined (Fig. 1A) found to be a key feature that enables it to inhibit YAP-dependent as reported (3). Conversely, the levels of Amot130 increased between 24 and 30 h, unlike AmotL1, which was unchanged. signaling and cell growth. fi breast cancer | Itch | growth control Signi cance fi he Hippo signaling pathway integrates changes in the cellular This study de nes a unique mechanism controlling the activa- microenvironment such as cell–cell contacts (1) and levels of tion of Hippo signaling and consequent inhibition of cell T fi mitogenic lipids (2, 3) to control cell growth and survival (4). During growth. Speci cally, serum starvation is found to induce the development, Hippo signaling regulates organ size (5), whereas in large tumor suppressor (LATS)1/2 kinases to phosphorylate and adults it has tumor-suppressive effects (6). Canonical Hippo sig- thus stabilize the 130 kDa isoform of the membrane-associated naling entails the activation of the mammalian STE20-like (MST) polarity protein angiomotin (Amot130). As a consequence, 1/2 protein kinases, which phosphorylate and activate the large Amot130 recruits the E3 protein-ubiquitin ligase atrophin-1 tumor suppressor (LATS)1/2 protein kinases. Active LATS1/2 interacting protein 4. This multiprotein complex then signals the phosphorylate YAP (Yes-associated protein) (7) and TAZ (tran- degradation of Yes-associated protein (YAP) and the inhibition of cell growth. These findings significantly modify our current scriptional coactivator with a PDZ-binding motif) to trigger their view that YAP phosphorylation by LATS1/2 is sufficient for its binding to 14-3-3 proteins and repression of their protranscriptional inhibition in mammals and thus for growth arrest. activities (8–11). Active YAP and TAZ are primarily nuclear, where they coactivate the TEAD family of growth-promoting transcrip- Author contributions: J.J.A., D.E.J., W.P.R., A.H., and C.D.W. designed research; J.J.A., D.E.J., tion factors (12) and the proapoptotic transcription factor p73 L.R.B., W.P.R., and C.D.W. performed research; J.J.A., D.E.J., B.L.H., L.R.B., M.D.C., Y.S., and (13). Recently, actin dynamics induced by the loss of cell attachment A.H. contributed new reagents/analytic tools; J.J.A., D.E.J., M.D.C., and C.D.W. analyzed (14) or matrix stiffness (15, 16) have also been shown to regulate data; and J.J.A. and C.D.W. wrote the paper. YAP and TAZ through LATS1/2-dependent and -independent The authors declare no conflict of interest. mechanisms. However, the mechanisms relating the different *This Direct Submission article had a prearranged editor. modes of regulation of YAP are unclear. 1To whom correspondence should be addressed. E-mail: [email protected]. Angiomotin (Amot) is a member of a structurally related family This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. of adaptor proteins that also includes AmotL1 and AmotL2 that 1073/pnas.1308236110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1308236110 PNAS Early Edition | 1of6 Downloaded by guest on September 24, 2021 A Serum Starved (Hours) The phosphorylation of Flag-tagged wild-type Amot130 versus 0 1 3 6 9 1224262830 Flag-tagged Amot130 (S175A) mutant by purified LATS2 and Amot130 immunoprecipitated Flag-tagged LATS1 activated with MST2 IB: Amot was measured as described (27). Wild-type Amot130 was phos- Amot130 / GAPDH 1.0 0.9 0.8 0.90.9 1.0 1.3 1.3 1.5 1.5 phorylated 10-fold more than Amot130 (S175A) by LATS2 and IB: AmotL1 over 2-fold more by LATS1 (Fig. 2C and Fig. S2B). IB: pS909- The 14-3-3 family of proteins binds specifically to phosphor- LATS1 ylated serine residues (28), including phospho-Ser-127 in YAP pS909-LATS1 / 1.0 0.5 0.4 0.81.1 0.9 2.5 2.3 1.6 0.5 Total LATS1 (1). Based upon similarity with Amot130 Ser-175 (Fig. S2C), the IB: LATS1 ability of LATS1 to induce 14-3-3 binding to this site was de- fined. Endogenous association of Amot130 with 14-3-3 was IB: YAP fi YAP / GAPDH 1.0 1.0 1.0 1.21.2 1.1 0.6 0.7 0.5 0.0 con rmed by immunoprecipitation of pan 14-3-3 with Amot from HEK 293T cells grown to high density (Fig. S2D). The IB: TAZ coimmunoprecipitation of YFP-tagged Amot130 with Flag-tag- TAZ / GAPDH 1.0 0.8 1.0 1.31.4 1.2 0.5 0.7 0.5 0.1 ged 14-3-3γ was then found to be induced in cells expressing IB: GAPDH MST2 and LATS1, but not from cells expressing either kinase in isolation or control vector (Fig. 2D). This is consistent with the B C low phosphorylation of exogenously expressed LATS1 in the N=4 N=3 0.8 *** ** 1.2 absence of coexpressed MST2 (Fig. S2E). Further, 14-3-3γ failed ** γ 0.6 0.8 to bind Amot130 (S175A) (Fig. 2E). Thus, the binding of 14-3-3 0.4 0.4 0.2 Steady State Levels 0.0 0.0 Normalized Amot130 Normalized Amot130 Steady State Levels Consensus LATS Recognition Motif Serum Starved - 24 h 24 h shControl + - A AmotL1(S262) Add Back of -+ 10 % Serum - - 5 min shLATS1 HVRSLS(175) AmotL2(S159) PDZ Binding P- Y 1 P- Y 2 P- Y 3 Motif Fig. 1. Serum starvation and LATS1 increase Amot130 protein levels. (A) The Amot130 ACCH Domain levels of endogenous proteins at the indicated times after initiation of serum LPTY PPEY PPEY Amot80 starvation were measured by immunoblot (IB) from lysates of MDA-MB-468 YAP2 AIP4 cells. Pixel intensities of endogenous proteins normalized to GAPDH and the Flag-Amot130 ++-- + - ratios of phosphorylated Ser-909 (pS909) LATS1 to total LATS1 are provided. B C Flag-Amot130 -+- + -+ (B) A graph of the mean ratios of endogenous Amot130 to GAPDH from four N=3 n.d. (S175A) 800 experiments (n = 4) from HEK 293T cells grown in DMEM with 10% serum or 2 ** GST-LATS2 -- - - ++ following 24 h of no serum followed by add back of DMEM containing 0% or Flag-LATS1 & YFP-MST2 - - ++-- 10% serum for 5 min.
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