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Table 1 Post-translational modification controlling hippo pathway core components

From: New insights into posttranslational modifications of Hippo pathway in carcinogenesis and therapeutics

Core component (D. melanogaster protein)

Enzyme

Regulatory sites

Function

MST1/2 (Hpo)

PI3K/Akt1

T120-p, T387-p

Prevention of caspase-mediated cleavage of MST1

Autophosphorylation

T183-pa

MST activation

JNK1

S82-p

Enhancement of MST1-mediated pro-apoptotic signaling

mTOR

T120-p

Loss of MST1 function

c-Abl

Y433-p

Inhibition of degradation

TAO3b

 

MST activation

PP2A

T183-depa

 

CHIP

Ubiquitination

Protein degradation

SAV1 (Sav)

MST2 

T26-p, S27-p, S36-p, S269-p

Activation

SIK2 and SIK3

S413-pc

Antagonizing Hpo pathway activity

LATS1/2(Wts)

MST1/2

s909-p, T1079-pd

Enzymatic activity

NUAK1 

s464-p

Protein stability

KIBRA

T1079-pd

Kinase activity

Itch

Ubiquitination

Protein degradation

CRL4DCAF1

Ubiquitination

Protein degradation

LATS1

WWP1

Ubiquitination

Protein degradation

Nedd4

Ubiquitination

Protein degradation

LATS2

CHK1/2

S408-p

Cell cycle regulation, apoptosis

SIAH1/2

Ubiquitination

Protein degradation

Aurora A

S83-p, S380-p

Intracellular localization

MOB1A, MOB1B (Mats)

MTS1/2

T12-p, T35-p, T74-p

Molecular association

praja2

Ubiquitination

Protein degradation

YAP (Yki)

LATS1/2

S61-p, S109-p, S164-p

The cytoplasmic retention

S127-p

The binding of 14-3-3 

S397-pe

Facilitates the binding of CK1δ/ε, leading to further serine phosphorylations

CK1ε/δ

S400-p, S403-pf

Generates a “phosphodegron” together with S397

c-Abl

Y407-pg

Promotes p73-dependent pro-apoptotic transcription

Src/YES1

Y407-p

Induces assembly of the β-catenin–YAP complex

CDK1

T119-p, S289-p, S367-p

Cell cycle regulation

NDR1/2

S127-p

The cytoplasmic retention

JNK

T119-p, S138-p, T154-p, S317-p, T362-p

Inducing YAP to play dual role in different cell contexts

SCFβ-TRCP

Ubiquitination

Protein degradation

Fbxw7

Ubiquitination

Protein degradation

Set7

K494-me

Cytoplasmic retention

CBP/p300

K494-ac; K497-ac

Altered nuclear activity

PML

K97-sumo, K280-sumoh

Stabilizes YAP1 by sumoylation and enhances p73-dependent transcription

TAZ

LATS1/2

S66-p, S117-p

Cytoplasmic retention

S89-p

The binding of 14-3-3 

S311-p

Facilitates the binding of CK1δ/ε, leading to further serine phosphorylations

GSK3-beta

S58-p, S62-p

Degradation

NEK1/CK1ε/δ

S314-p

Degradation/β-TrCP recruitment

c-Abl

Y321-p

Altered nuclear activity

PP1

S89-dep,S311-dep

Promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase

  1. The Hippo pathway acts primarily by inhibiting the nuclear functions of YAP and TAZ. Main PTMs of core components are described in Fig. 2; Table 1.)
  2. p phosphorylation; dep dephosphorylation; me methylation; ac acetylation; sumo sumoylation
  3. a T180-p in MST2
  4. b Tao1 phosphorylates T195-p of Hpo
  5. c Phosphorylation of Sav at Ser 413 in Drosophila
  6. d Thr1079 in Lats1 and Thr1041 in Lats2
  7. e S381 of YAP1 iso2 corresponds to S397 of YAP1
  8. f S384, S387 of YAP1 iso2 corresponds to S400, S403 of YAP1
  9. g Y357 of YAP1 iso3 corresponds to S407 of YAP1
  10. h K242 of YAP1 iso3 corresponds to K280 of YAP1