Cadherins

Cadherin
signaling

Glycogen synthase kinase (GSK-3beta)
GSK-3β
Akt/PKB
ILK
Dsh
p90RSK
PI-3 kinase
Wnt
ERK
Glycogen
synthase
CyD
c-jun
β-catenin
Integrins

Cadherins and integrins crosstalk

Tyrosine phosphorylation of β-catenin

Phosphorylation in cadherin-dependent contacts

Cadherin regulation

Wnt signaling

Major morphogens:
- Wnts
- Hedgehogs
- Notch ligands (Delta-like/Jugged)
- BMPs (Bone Morphogenic Proteins)
- FGFs
- Retinoids

Wnt palmitoylation

Wnt signaling to β-catenin

More Wnt
signaling
to β-catenin

Wnt
signaling
to Ca
and Rho

Hedgehog signaling

Mammalian hedgehogs:
- Sonic hedgehod (SHH)
- Indian hedgehog (IHH)
- Desert hedgehog (DHH)

Hedgehog modifications

Hedgehog modifications

Hedgehog secretion

Hedgehog signaling

hWIF and Shifted

Notch signaling

Delta-Notch signaling

Notch signaling
- Delta-like/Jugged: Dll 1,3,4, Jag1,2 — canonical ligands
- Notch - receptor
- ADAM (TACE, Kuzbanian) – metalloprotease for S2 cleavage
- γ-secretase complex (presenilin-containing) for S3 cleavage
- NICD, or NICD, or ICN – transcriptionally active Notch fragment
- CSL, CBF1/RBPJk, SuH (suppressor of hairless) – transcription factor

HIF-1 enhances Notch(ICN)-dependent
transcription

TGFβR-family receptors

TGFβ-family ligands and receptors

TGFβ-family ligands

TGFβ signaling and crosstalk with EGFR

TGFβ/Activins
co-receptors

Smad proteins

TGFβ to p21Waf1 and p15Ink4B

TβR-V signaling

TβR-I,II and V signaling

TGFβ-induced growth arrest

Signaling to gastrulation

STRESS SIGNALING

Reactive oxygen species

Reactive oxygen species

ROS levels
1) Moderate (mostly by NADPH-oxidase to GF, cytokines, TNFα-like ligands; needed for mitogenic signaling)
2) High (mostly stress-induced; usually pro-apoptotic)
3) The highest – a consequence of mitochondrial disfunction during apoptosis

Oxidative modifications of proteins

Signaling targets of ROS
- Tyrosine phosphatases

Cell damage targets of ROS
- Tyrosine phosphatases
- Proline hydroxylase (PHD)

Signaling targets of ROS
- Tyrosine phosphatases
- Proline hydroxylase (PHD)

HIF-1

ROS in HIF-1 signaling

Signaling targets of ROS
- Tyrosine phosphatases
- Proline hydroxylase (PHD)
- ASK-1 (via thioredoxin)
- JNK (via GSTp)
- PKC
- Ras
- IKK (to NFkB)
- AP-1, p53 (via Ref-1)

NO

NO-synthases
- iNOS (inducible)
- eNOS (endothelial)
- nNOS (neuronal)

Mechanisms of NO action
- S-nitrosylation of proteins
- peroxynitryl formation
- co-factor for soluble guanylate cyclase

NO and regulation of cGMP synthesis