The action of
protein kinases and
protein phosphatases is essential for multiple physiological responses. Each
protein kinase displays its own unique substrate specificity, and a regulatory mechanism that may be modulated by association with other
proteins.
Protein kinases are classified by the target
amino acid in their substrates. Some
protein kinases can phosphorylate both
serine/
threonine, as well as
tyrosine residues. This group of
kinases has been known as dual specificity
kinases. Unlike the dual specificity
kinases, a heterogeneous group of
protein phosphatases are known as
dual-specificity phosphatases. These
phosphatases remove
phosphate groups from
tyrosine and
serine/
threonine residues on their substrate.
Dual-specificity phosphatases are important signal transduction
enzymes that regulate various cellular processes in coordination with
protein kinases. The
protein kinase-
phosphoproteins interactions play an important role in
obesity . In
obesity, the pro- and anti-inflammatory effects of
adipokines and
cytokines through intracellular signaling pathways mainly involve the
nuclear factor kappa B (
NF-kappaB) and the
c-Jun N-terminal kinase (JNK) systems as well as the inhibitor of kappaB-
kinase beta (
IKK beta). Impairment of
insulin signaling in
obesity is largely mediated by the activation of the IKKbeta and the JNK. Furthermore, oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses
insulin biosynthesis. Additionally,
obesity-activated
calcium/calmodulin dependent-protein kinase II/p38 suppresses
insulin-induced
protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors,
RNA-dependent protein kinase-like ER eukaryotic initiation factor-2alpha
kinase (PERK) and activating transcription factor-6. The transcriptional regulation of adipogenesis in
obesity is influenced by AGC (
protein kinase A (PKA), PKG, PKC) family signaling
kinases.
Obesity may induce systemic oxidative stress and increase
reactive oxygen species in adipocytes. Increase in intracellular oxidative stress can promote
PKC-beta activation. Activated
PKC-beta induces
growth factor adapter Shc phosphorylation. Shc-generated
peroxides reduce mitochondrial oxygen consumption and enhances
triglyceride accumulation.
Obesity is fundamentally caused by cellular energy imbalance and dysregulation. Like
adenosine monophosphate (
AMP)-activated protein kinase (AMPK) and
mammalian target of rapamycin (mTOR), N-terminal Per-ARNT-Sim (
PAS) kinase are nutrient responsive
protein kinases and important for proper regulation of
glucose metabolism in mammals at both the hormonal and cellular level. Defective responses of AMPK to
leptin may contribute to resistance to
leptin action on food intake and energy expenditure in obese states.