Tissues and organs can both produce and respond to physical forces. For example, the lungs expand and contract; the heart pumps blood; and bones and muscles grow or shrink depending on how much they are used. These responses are possible because cells contain proteins that can respond to physical forces. One of the best studied of these is a protein called β-catenin, which increases the activity of genes that trigger cells to divide to promote the expansion of tissues. β-catenin is over-active in many types of cancer cells where it contributes to tumor growth. In addition to being switched on by mechanical force, β-catenin is also activated when cells detect a signal molecule called Wnt.

Cells cycle through a series of stages known as the cell cycle to ensure that they only divide when they are fully prepared to do so. Benham-Pyle et al. investigated if physical force and Wnt activate β-catenin in the same way or if they have different effects on cell division. The experiments were conducted on dog kidney cells that had left the cell cycle and had therefore temporarily stopped dividing. Physical forces, such as stretching, resulted in β-catenin being modified by an enzyme called SRC kinase, which allowed the cells to re-enter the cell cycle. On the other hand, Wnt stabilized β-catenin and temporarily increased the number of cell divisions.

When mechanical stretch and Wnt signaling were combined, the cells were more likely to re-enter the cell cycle and divide compared to either stimulus alone. These data suggest that physical force and Wnt signaling affect β-catenin differently and that they can therefore have a greater effect on cell or tissue growth when they act together than on their own.

The findings of Benham-Pyle et al. show that β-catenin is not simply switched on or off, but can have different levels of activity depending on the input the cells are receiving. Future experiments will test whether these mechanisms also exist in three-dimensional tissues, which will help us understand how organs develop.

Mechanical cues are critical for regulating cellular growth, morphology, and behavior in developing and adult tissues. Recently, cadherin-mediated cell-cell adhesions have been identified as core components that regulate the response of multicellular tissues to externally applied strain (Whitehead et al., 2008; Desprat et al., 2008; Kim et al., 2011). Significantly, the cadherin-associated transcriptional co-activator β-catenin accumulates in the nucleus following mechanical strain (Farge, 2003; Benham-Pyle et al., 2015).

β-Catenin transcriptional activity drives cellular proliferation and is a downstream effector of the Wnt signaling pathway (Nelson and Nusse, 2004; Clevers and Nusse, 2012). β-Catenin protein levels in cells are tightly controlled by sequestering β-catenin at cell-cell contacts and active degradation of cytosolic β-catenin (Whitehead et al., 2008; Desprat et al., 2008; Kim et al., 2011; Aberle et al., 1997; Ikeda et al., 1998; Su et al., 2008). The E-cadherin-bound pool of β-catenin is regulated by a balance of tyrosine kinase and tyrosine phosphatase activities (Farge, 2003; Benham-Pyle et al., 2015; Muller et al., 1999; Piedra et al., 2001; Lilien and Balsamo, 2005; Tan et al., 2016). The affinity between E-cadherin and β-catenin at junctions is decreased by the activity of cytoplasmic and receptor tyrosine kinases (EGFR, Src, Abl, Fyn/Fer) (Nelson and Nusse, 2004; Clevers and Nusse, 2012; Matsuyoshi et al., 1992; Takeda et al., 1995; Coluccia et al., 2007; Krejci et al., 2012) and increased by the activity of tyrosine phosphatases (PTB1B, SHP-3, PTP, LAR) (Lilien and Balsamo, 2005; Tan et al., 2016; Sap et al., 1994; Hellberg et al., 2002; Xu et al., 2002). In normal epithelia, cytoplasmic levels of β-catenin are very low due to targeting of β-catenin for degradation through β-catenin phosphorylation on Serine 45 by Casein Kinase I (CKI), which primes β-catenin for the further phosphorylation of Serine 33, Serine 37, and Threonine 41 by Glycogen Synthase Kinase 3β (GSK3β) (Aberle et al., 1997; Amit et al., 2002; Liu et al., 2002). CKI/GSK3β phosphorylated β-catenin is ubiquitinated within the Axin/Adenomatous Polyposis coli complex, and then degraded in the proteasome (Winston et al., 1999).

Accumulation of cytosolic β-catenin can be triggered by Wnt, the mammalian homolog of Drosophila Wingless. When Wnt ligand binds to Frizzled/LRP receptors, Axin is recruited to the plasma membrane and CKI/GSK3β are inactivated, resulting in inhibition of β-catenin ubiquitination and degradation (Li et al., 2012; Vinyoles et al., 2014). As a result, β-catenin accumulates in the cytoplasm, translocates to the nucleus, and activates target gene transcription in a complex with Tcf/Lef (Clevers and Nusse, 2012). Wnt/β-catenin activation broadly promotes cell proliferation and tissue expansion during developmental patterning. Consequently, mis-regulation of the Wnt signaling pathway, particularly β-catenin degradation, and downstream β-catenin transcriptional activity disrupt contact-mediated cell cycle inhibition, drive epithelial to mesenchymal transition, and promote cellular transformation and cancer progression (Orford et al., 1999; Korinek et al., 1997; Clevers, 2006; Chen et al., 2012).

In addition to its known roles in cadherin-mediated cell-cell adhesion and as a downstream effector of Wnt-mediated proliferation, β-catenin is a mechanotransducer. Mechanical strain induces nuclear accumulation and increased transcriptional activity of β-catenin (Benham-Pyle et al., 2015; Sen et al., 2008), and mechanical perturbation of living tissues is associated with increased β-catenin signaling and induction of downstream transcriptional targets (Farge, 2003; Farge and development, 2011). β-Catenin transcriptional activation downstream of mechanical force or Wnt stimulation has been studied separately. It remains unknown whether β-catenin’s role as a target of mechanical force is independent, redundant or synergistic to Wnt signaling in tissue homeostasis.

Previously, we showed that mechanical strain drives the re-entry of a quiescent epithelial monolayer into the cell cycle by sequential, but independent induction of Yap1 (G0 to G1) and then β-catenin transcriptional activities (G1 to S): inhibition of Yap1 and β-catenin transcriptional activities was sufficient to block cell cycle entry and G1 to S transition, respectively (Benham-Pyle et al., 2015). However, cells that exit quiescence following mechanical strain accumulate in S/G2 and do not enter mitosis, suggesting that a further activation event is required to complete cell cycle progression. Here we show that mechanical strain-induced Src phosphorylation of β-catenin and Wnt3A pathway-dependent stabilization of cytoplasmic β-catenin synergize to increase β-catenin transcriptional activity to levels that drive cell cycle progression through S/G2 and mitosis.

Mechanical cues are critical for the normal development, morphology, and function of multicellular tissues. Numerous pathways and molecular scaffolds have been identified as mechano-responsive, including cadherin cell-cell adhesion complexes (Liu et al., 2010; Cai et al., 2014), integrin-mediated focal adhesions (Wang et al., 2001), the actin cytoskeleton (Hoffman et al., 2011; Engl et al., 2014), and Yap1 and β-catenin (Whitehead et al., 2008; Benham-Pyle et al., 2015; Aragona et al., 2013; Kamel et al., 2010; Dupont et al., 2011; Heo and Lee, 2011). Whether mechanical cues synergize with signaling pathways known to regulate development and homeostasis remains a relatively unexplored area of investigation. Previously, we reported that mechanical strain sequentially induced Yap1 and β-catenin transcriptional activity to drive cell cycle re-entry (Yap1) and progression from G1 into S (β-catenin) (Benham-Pyle et al., 2015). Here, we show that these cells are held in S/G2 and do not enter mitosis, and that further activation of the Wnt signaling pathway and β-catenin transcriptional activity are required to drive cell cycle progression through mitosis.

The accumulation of mechanically strained cells in S/G2 did not appear to be caused by the activation of the DNA damage checkpoint, as the level of DNA damage and DNA repair pathway activation in those cells, measured by levels of phospho-γH2A.X, p53 and p53BP1, was insignificant compared to that induced by a DNA damaging agent and present in actively cycling cells (Figure 2). In vivo, G2 delay prior to mitosis has been identified in select developmental niches, including early stages of Drosophila development (Edgar, 1990), the Drosophila zone of non-proliferating cells (ZNC) (Johnston and Edgar, 1998), and during Drosophila neural fate determination (Nègre et al., 2003). Our results indicate that quiescent cells may have evolved regulatory mechanisms to arrest healthy cells in S/G2 under circumstances unfavorable for mitosis; for example, mitosis at high cell density might result in the extrusion of cells and the disruption of monolayer integrity.

β-Catenin is a well-characterized regulator of cell cycle progression (Nelson and Nusse, 2004; Orford et al., 1999; Morkel et al., 2003; Olmeda et al., 2003), and is responsive to mechanical cues (Farge, 2003; Benham-Pyle et al., 2015; Brunet et al., 2013). While mechanical strain-induced activation of β-catenin transcriptional activity requires E-cadherin trans adhesion interactions (Benham-Pyle et al., 2015), it remains unclear whether mechanical strain induces β-catenin transcriptional activity through destabilizing the junctional pool of cadherin-bound β-catenin, or stabilizing cytoplasmic β-catenin, or a combination of both.

Here, we showed that mechanical strain induced a Src-dependent increase in tyrosine phosphorylated (pY654) β-catenin in the cytoplasm and nucleus. pY654 β-catenin has a weaker affinity for E-cadherin (Huber and Weis, 2001; Zeng et al., 2006), and thus may be released from the cadherin complex into the cytoplasm as indicated by the increased cytoplasmic staining of pY654 β-catenin in mechanically strained monolayers (Figure 3E). Importantly, SU6656 inhibition of Src activity completely blocked the strain-induced increases in Y654 β-catenin phosphorylation, β-catenin accumulation in the cytoplasm and nucleus, β-catenin transcriptional activity, and DNA replication (Figure 3). Nevertheless, we also tested the possibility that other tyrosine kinases were involved in cellular responses to mechanical strain (Lilien and Balsamo, 2005; Tamada et al., 2012; Bays et al., 2014). Indeed, inhibition of EGFR partially reduced the strain-induced increase in level of pY654 β-catenin, but did not significantly affect the strain-induced increase in β-catenin transcriptional activity or cell cycle re-entry (Figure 3—figure supplement 4 and 5). Since Src inhibition blocked strain-induced pY654 β-catenin accumulation, β-catenin transcriptional activity and cell cycle progression, we conclude that Src activation plays the predominant role in activating β-catenin signaling in response to mechanical strain. How Src is activated by strain is currently unknown. However, our earlier finding that E-cadherin trans adhesion interactions are required for mechanical strain-induced β-catenin transcriptional activity and cell cycle progression (Benham-Pyle et al., 2015) indicates that Src activation may be downstream of E-cadherin extracellular engagement.

In contrast to the effects of inhibiting Src activity, inhibition of CKI activity increased β-catenin transcriptional activity (Figure 4) independently of mechanical strain. Normally, CKI phosphorylation of β-catenin is the first step in targeting cytosolic β-catenin for degradation (Amit et al., 2002; Maher et al., 2009). Since CKI inhibition did not change the level of pY654 β-catenin following mechanical strain (Figure 4E,F), the effects of CKI inhibition and mechanical strain likely act through different biochemical pathways.

Live imaging of Fucci-MDCK monolayers revealed that increased β-catenin transcriptional activity upon CKI inhibition produced a distinct cell cycle response to mechanical strain compared to un-treated monolayers (Figures 5 and 6). Following mechanical strain, CKI inhibition increased both the number of cells that accumulated in S/G2 and the number of mitotic events. However, only cells exposed to both CKI inhibition and mechanical strain re-entered the cell cycle and divided within 24 hr. Importantly, this increase in mitotic events was dependent on β-catenin transcriptional activity. Components of the β-catenin degradation machinery are commonly mutated in tumors (Morin et al., 1997; Bottomly et al., 2010; Mishra et al., 2015), and inactivation of β-catenin degradation is thought to be an important event in tumor development. However, it has remained unclear what additional factors may be important for metastasis and malignant growth. Our results indicate that mechanical strain may trigger accelerated growth within a mutation-induced, pre-malignant background of increased β-catenin transcriptional activity.

CKI inhibition is a simple method to stabilize cytoplasmic β-catenin by short-circuiting the β-catenin degradation machinery, but it has the potential for off-target effects given the broad functions of CKI in cells. Wnt ligands are secreted signaling proteins that induce β-catenin transcriptional activity by inhibiting β-catenin phosphorylation by CKI/GSK3β (Li et al., 2012; Vinyoles et al., 2014). In the absence of mechanical strain, Wnt3A stimulation of quiescent MDCK monolayers was not sufficient to drive cell cycle re-entry or an accumulation of cells in S/G2. Note also that levels of pY654 β-catenin were also unchanged in the presence of Wnt3A (Figure 7—figure supplement 1), similar to CKI inhibition (Figure 4E,F), indicating a Wnt-independent pathway for Src activation. Upon mechanical strain, Wnt3A-stimulated monolayers had significantly higher numbers of cells both in S/G2 and entering mitosis compared to monolayers treated with Wnt3A or mechanical strain alone (Figures 7 and 8). The linear increase in mitotic events after an 8–10 hr delay following mechanical strain in the presence of Wnt3A is consistent with the hypothesis that monolayers exposed to both mechanical strain and Wnt3A exited quiescence (G0), proceeded through DNA replication and then divided without a delay in S/G2. This is in sharp contrast to mechanically strained monolayers without Wnt3A stimulation that accumulated in S/G2.

Dose-dependent effects and signaling thresholds have been previously described in early development (Green and Smith, 1990; Green et al., 1992; Zhang et al., 2013), and several signaling pathways, including Wnt/β-catenin signaling, have been suggested to function as continuously variable signaling pathways (Hazzalin and Mahadevan, 2002; Bardwell, 2008; Goentoro and Kirschner, 2009). Our results showed that mechanical strain or Wnt3A addition activated β-catenin signaling to a level sufficient to drive some cells through G1 into S (Figure 1, Figure 7D). However, the combination of mechanical strain and Wnt3A addition induced higher β-catenin signaling levels (Figure 7—figure supplement 1), which drove more cells through G1 into S (Figure 7) and through G2 into mitosis (Figure 8). This synergistic effect of Wnt3A and mechanical strain on both β-catenin transcriptional activity and cell cycle progression confirms that Wnt/β-catenin activity is not a stable binary switch, but rather involves a graded activation in which different levels of β-catenin transcriptional activity produce different cell cycle responses (lower for G1 to S/G2, and higher for S/G2 into mitosis).

It has been a long-standing hypothesis that growth-induced local mechanical cues could influence morphogenesis by modulating growth rates, the direction of growth, or differentiation (Henderson and Carter, 2002). Indeed, a model integrating both force-sensing and signaling pathways accounted for experimentally observed patterns of growth, cell shape, and cell size In the Drosophila wing imaginal disc (Aegerter-Wilmsen et al., 2012). This model was supported by the observation that a global pattern of stress in the wing imaginal disc coincided with polarized actomyosin contractility in the cell cortex and the alignment of the division plane with the main axis of cell stretch, thereby contributing to tissue elongation. However, very few studies have demonstrated how mechanical forces could synergize with signaling pathways to effect growth rates.

How might Wnt signaling and mechanical forces synergize in vivo? Canonical Wnt signaling can act as a locally restricted morphogen to regulate limb development, asymmetric stem cell divisions, and sensitivity to other effector pathways during development and adult tissue homeostasis.(Ng et al., 1996; Habib et al., 2013; Lindsley et al., 2006; Alexandre et al., 2014). In mammary and feather morphogenesis, local Wnt signaling is required for proper appendage bud formation and local morphogenesis from a flat epithelium; increasing Wnt activation results in randomized and expanded growth zones and ectopic bud formation (Widelitz et al., 1999; Chu et al., 2004). Similarly, Wnt signaling defines localized growth zones during liver development and regeneration (Suksaweang et al., 2004) and expression of a constitutively active β-catenin expands local growth zones and stem cell populations and increases total liver size (Blanchard et al., 2009). Our results indicate that local Wnt signaling in a tissue experiencing moderate levels of global mechanical strain could result in local hotspots of mitosis through increased levels of Wnt/β-catenin signaling.

Levels of strain higher than those applied here have been observed during dorsal closure, germband extension, and neurulation in Drosophila and zebrafish (Blanchard et al., 2009). Thus, in tissues experiencing high levels of strain (30–50% strain), cell division and tissue expansion may not require Wnt signaling. Indeed, in quiescent MDCK monolayers, 50% uni-axial stretch was sufficient to increase the fraction of cycling cells and number of cell divisions Streichan et al. (2014). Therefore, while high levels of Wnt signaling and mechanical force could independently drive proliferation and tissue expansion, growth-generated mechanical forces during development could also combine with local (Wnt) signaling to refine areas of growth during tissue morphogenesis and during adult tissue repair.

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Author details

1. Blair W Benham-Pyle

   Program in Cancer Biology, Stanford University, Stanford, United States

   Contribution

   BWB-P, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   No competing interests declared.

2. Joo Yong Sim

   Department of Mechanical Engineering, Stanford University, Stanford, United States

   Present address

   Electronics and Telecommunications Research Institute, Daejeon, Republic of Korea

   Contribution

   JYS, Design of Biaxial Live Cell Stretcher, Drafting or revising the article

   Competing interests

   No competing interests declared.

3. Kevin C Hart

   Department of Biology, Stanford University, Stanford, United States

   Contribution

   KCH, Fluorescent Bead Calibration of Biaxial Live Cell Stretcher, Drafting or revising the article

   Competing interests

   No competing interests declared.

4. Beth L Pruitt

   1. Department of Mechanical Engineering, Stanford University, Stanford, United States
   2. Stanford Cardiovascular Institute, Stanford University, Stanford, United States
   3. Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States

   Contribution

   BLP, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   No competing interests declared.

   "This ORCID iD identifies the author of this article:" 0000-0002-4861-2124

5. William James Nelson

   1. Program in Cancer Biology, Stanford University, Stanford, United States
   2. Department of Biology, Stanford University, Stanford, United States
   3. Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States

   Contribution

   WJN, Conception and design, Drafting or revising the article

   For correspondence

   wjnelson@stanford.edu

   Competing interests

   WJN: Reviewing editor, eLife

   "This ORCID iD identifies the author of this article:" 0000-0003-3039-3776

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