Common Signaling Pathways in Mechanotransduction

Cellular mechanotransduction

The process by which cells convert mechanical signals into biochemical responses.

Focal Adhesion Kinase (FAK) Pathway

Converts mechanical forces at the extracellular matrix (ECM) into intracellular signaling cascades.

Focal Adhesions (FAs)

Mechanosensors linking integrins to the cytoskeleton.

FAK Activation

Integrins cluster in response to ECM stiffness, activating FAK autophosphorylation at Y397.

Phosphorylated FAK

Recruits Src kinase, amplifying downstream signaling.

FAK-Ras-MAPK pathway

Promotes cell survival and proliferation.

FAK-PI3K-Akt pathway

Regulates cell adhesion and migration.

FAK-YAP/TAZ crosstalk

Activates YAP/TAZ via cytoskeletal remodeling.

Mechanotransduction Relevance in Cancer

Elevated FAK signaling enhances metastasis by promoting cell invasion.

Mechanotransduction Relevance in Fibrosis

FAK signaling contributes to myofibroblast activation in stiff ECM.

YAP/TAZ (Hippo) Pathway

Transcriptional co-activators that respond to mechanical cues, controlling gene expression.

Mechanosensitive Activation of YAP/TAZ

Under soft ECM conditions, YAP/TAZ are phosphorylated by LATS1/2, preventing nuclear localization.

YAP/TAZ translocation

Under stiff ECM conditions, actin cytoskeleton tension inhibits LATS1/2, allowing YAP/TAZ to enter the nucleus.

YAP/TAZ-TEAD interaction

Activates genes related to proliferation, survival, and ECM remodeling.

Crosstalk with β-catenin

Enhances stem cell differentiation.

Mechanotransduction Relevance in Cancer (YAP/TAZ)

YAP/TAZ is a key driver of tumor growth and metastasis in stiff microenvironments.

Mechanotransduction Relevance in Fibrosis (YAP/TAZ)

Increased YAP/TAZ activity drives fibroblast-to-myofibroblast differentiation.

RhoA/ROCK Pathway

Regulates actin cytoskeleton organization in response to mechanical forces.

Activation Mechanism of RhoA/ROCK

Mechanical stress activates RhoA GTPase, which in turn activates ROCK (Rho-associated kinase).

ROCK phosphorylates MLC

Promotes actomyosin contraction.

Downstream Effects of RhoA/ROCK

Actin polymerization and stress fiber formation; enhances focal adhesion stability via vinculin and talin recruitment.

Mechanotransduction Relevance in Cancer (RhoA/ROCK)

Increased RhoA/ROCK signaling promotes cell migration and metastasis.

Fibrosis

RhoA/ROCK activation increases myofibroblast contraction and ECM stiffening.

Function of Rho-Associated Kinases (ROCK)

Controls ECM remodeling and fibrosis through mechanotransduction.

Activation Mechanism of TGF-β

TGF-β is sequestered in the ECM and released by mechanical forces (e.g., ECM stiffening).

TGF-β Receptors

TGF-β binds TGF-β receptors (TβRI/TβRII), leading to SMAD2/3 phosphorylation.

SMAD2/3 Phosphorylation

Phosphorylated SMAD2/3 complexes with SMAD4, translocates into the nucleus, and regulates gene expression.

Downstream Effects of TGF-β

Promotes fibrosis by upregulating α-SMA, collagen, and fibronectin.

Crosstalk with YAP/TAZ

Crosstalk with YAP/TAZ and β-catenin enhances pro-fibrotic signaling.

Mechanotransduction Relevance in Fibrosis

Excessive TGF-β/SMAD activation leads to myofibroblast differentiation and ECM deposition.

Mechanotransduction Relevance in Cancer

TGF-β plays dual roles, acting as a tumor suppressor in early stages and a metastasis promoter in later stages.

β-Catenin/Wnt Pathway Function

Regulates cell fate, differentiation, and adhesion in response to mechanical cues.

Activation Mechanism of β-Catenin

Under low mechanical stress, β-catenin is degraded by the Axin-APC-GSK3β complex.

High Mechanical Stress Effect

Under high mechanical stress, Wnt ligands bind Frizzled receptors, leading to β-catenin stabilization.

β-Catenin Accumulation

β-catenin accumulates in the nucleus and activates transcription factors (LEF/TCF).

Crosstalk with Mechanotransduction in β-Catenin

Integrins and cadherins regulate β-catenin stability in response to force.

Stem Cell Differentiation

Stiff matrices promote osteogenic differentiation via β-catenin.

Notch Pathway Function

Controls cell differentiation and fate decisions through direct cell-cell mechanical signaling.

Activation Mechanism of Notch

Ligand-receptor interaction (Notch-Delta/Jagged) is mechanically regulated.

Notch Cleavage

Under force, Notch undergoes proteolytic cleavage, releasing Notch Intracellular Domain (NICD).

NICD Function

NICD translocates into the nucleus to regulate gene expression.

Crosstalk with Mechanotransduction in Notch

Integrins and cytoskeletal tension enhance Notch signaling.

ERK/MAPK Pathway Function

Mediates cell proliferation, differentiation, and survival in response to mechanical forces.

Activation Mechanism of ERK

Shear stress, ECM stiffness, and integrin activation lead to FAK-Src-Ras signaling.

Ras-GTP Activation

Ras-GTP activates Raf (MAPKKK) → MEK1/2 (MAPKK) → ERK1/2 (MAPK).

ERK Translocation

ERK translocates to the nucleus, activating transcription factors like c-Myc, AP-1.

Relevance of ERK in Cancer

ERK overactivation promotes tumor proliferation and drug resistance.

Fibrosis

ERK regulates fibroblast activation and ECM deposition.

FAK (Focal Adhesion Kinase)

Activated when integrins bind ECM proteins, triggering FAK autophosphorylation and recruiting Src kinase.

PI3K-Akt

A downstream pathway activated by FAK that is involved in survival.

Ras-ERK

A downstream pathway activated by FAK that is involved in proliferation and migration.

YAP/TAZ

Transcriptional control that regulates stiffness-dependent gene expression.

RhoA/ROCK

Controls actin tension and focal adhesions, involved in cytoskeletal dynamics.

TGF-β/SMAD

Promotes fibrosis and interacts with YAP/TAZ for ECM remodeling.

β-Catenin/Wnt

Stiffness promotes osteogenic lineage differentiation.

Notch

Regulates force-dependent differentiation and cell-cell communication.

ERK/MAPK

Regulates cell proliferation, differentiation, and survival.

Mechanotransduction

Integrates signals from ECM stiffness, shear stress, and integrins to activate gene transcription and cytoskeletal remodeling.

LATS1/2 kinase

Inactivated in a stiff ECM, allowing YAP/TAZ to promote proliferation and survival.

Actomyosin contraction

Stimulated by ROCK phosphorylation of myosin light chain (MLC), enhancing focal adhesion stability.

Integrins

Proteins that mediate cell-ECM adhesion and are involved in mechanotransduction.

Mechanical force

Stimulates RhoA activation, leading to cytoskeletal contraction.

ECM stiffness

Cells sense ECM stiffness through integrins and cytoskeletal tension.

Tumor cell invasion

Blocking integrins may be a better strategy than inhibiting FAK directly.

Scar tissue fibroblasts

Often have high RhoA/ROCK activity due to mechanical force responses.

Cell migration ability

Would be impaired if FAK is permanently activated, leading to no focal adhesions.

FAK inhibitor

Could affect cancer metastasis by inhibiting cell migration.

Soft ECM

Leads to YAP/TAZ phosphorylation and degradation, reducing proliferation.

Fibrotic diseases

Involve excessive tissue stiffening.

TGF-β

Sequestered in the ECM and released by mechanical stress or proteases.

SMAD2/3

Phosphorylated by TGF-β binding to TβRI/TβRII receptors.

SMAD4

Complexes with SMAD2/3 and translocates to the nucleus to activate fibrosis-related genes.

ERK

Activated by Ras, leading to cell division and survival.

c-Myc

Stimulated by active ERK to promote cell division.

AP-1

Activated by ERK to promote cell survival.

Notch signaling

Activated when Notch receptors interact with Delta or Jagged ligands.

YAP/TAZ

Nuclear translocation increases with stiff ECM, enhancing proliferation and survival.

LATS1/2

When activated in a stiff ECM, leads to decreased cell proliferation.

FAK

Promotes focal adhesion turnover and cytoskeletal dynamics.

Integrin clustering

When blocked, impairs FAK signaling and reduces cell adhesion, migration, and survival.

RhoA

Inhibition leads to breakdown of actin stress fibers and weaker adhesion.

ROCK

Increasing activity affects cell stiffness.

Mechanical stress

Can enhance Notch activation, leading to gene expression changes.

Tumor cell proliferation

Increases with hyperactive ERK.

Endothelial cells

Survive under high shear stress due to ERK activation.

Vascular graft

Mechanotransduction can be used to activate Notch signaling for endothelial cell differentiation.

Cell migration

Increases with permanently activated FAK.

Cancer metastasis

Reduced by FAK inhibitors preventing focal adhesion turnover.

TGF-β inhibitors

Might be used to treat fibrosis.

Shear stress

Can influence Notch activity in vascular endothelial cells.

Cell stiffness

Increases due to enhanced actomyosin contraction and focal adhesion reinforcement.

RhoA/ROCK

High activity in fibroblasts in scar tissue due to mechanical stiffness, activating RhoA/ROCK to maintain cytoskeletal tension and ECM remodeling.

TGF-β/SMAD

If TGF-β availability is reduced, SMAD2/3 phosphorylation would decrease, reducing fibrosis-related gene expression.

TGF-β/SMAD

TGF-β signaling would increase as mechanical stress enhances TGF-β release and receptor activation.

TGF-β/SMAD

TGF-β inhibitors may be used to treat fibrosis because fibrosis is driven by excessive ECM deposition via TGF-β signaling.

ERK/MAPK

If MEK is inhibited, ERK activation would be blocked, stopping downstream proliferation signals.

ERK/MAPK

If a tumor cell has hyperactive ERK, its proliferation rate would increase, as ERK drives cell cycle progression and survival.

ERK/MAPK

ERK activation helps endothelial cells survive under high shear stress by activating ERK via integrins.

Notch

If Notch signaling is blocked in a developing embryo, developmental defects would occur because Notch is essential for tissue differentiation and organogenesis.

Notch

Increased shear stress enhances Notch activation, promoting endothelial cell differentiation and vascular stability.