Role of PKA in cytoskeleton
reorganisation
A wide variety of soluble signaling mediators utilize the Protein
kinase cAMP-dependent (PKA) pathway to regulate cellular
processes including intermediary metabolism, ion channel conductivity, and transcription.
PKA plays a central role in cytoskeletal regulation and cell
migration. Moreover, the role of PKA in cytoskeletal
organization and cell migration, exerting both negative (i.e. inhibitory) and positive
(i.e. required or enhancing) effects.
GNAS complex locus coupled receptor (G-protein
alpha-s coupled receptor) interaction with
the trimeric G-protein alpha-s/Guanine nucleotide binding
protein beta and gamma (G-protein beta/gamma) causes the
exchange of GDP for GTP bound to G-protein alpha subunits
and the dissociation of the G-protein beta/gamma
heterodimers. G-protein alpha-s activates
Adenylate cyclases.
Upon stimulation, Adenylate cyclases
increase the level of Cyclic Adenosine 3',5'-monophosphate
(cAMP) in cells and activate the PKA-cat
and PKA-reg complex that results in
PKA activation [1].
Negative effects of PKA on cell migration
have been reported for integrin-dependent endothelial cell migration. Also,
matrix-specific down-regulation of
cAMP/PKA signaling appears to
be required for collagen-induced Actin synthesis and stress
fiber formation in endothelial cells [2].
PKA-dependent phosphorylation of complex
Integrin alpha 4 and beta 1 (Alpha-4/beta-1
integrin) is important for migration and
other integrin function. Phosphorylation of Alpha-4/beta-1
integrin blocks Paxillin binding, which
activates cell migration and increases lamellipodial stability [3].
The cytoskeletal regulatory protein Vasodilator-stimulated
phosphoprotein (VASP) localizes to focal adhesions, largely
through interaction with proteins such as Vinculin,
Zyxin, and KIAA1274.
PKA phosphorylates VASP and
disrupts its interaction with C-abl oncogene 1 receptor tyrosine kinase
(c-Abl) [4].
A relative newcomer to the list, the LIM and SH3 protein 1
(LASP1), was identified as a potential cytoskeletal
PKA substrate in gastric fibroblasts and gastric parietal
cells. LASP1 regulates its translocation to areas of dynamic
actin filaments synthesis. Phosphorylation of
LASP1 by PKA decreases its
interaction with Actin [5].
Adducins promote association of Spectrin
non-erythrocytic (Fodrin (spectrin)) with
Actin to facilitate capping of the fast growing end of
Actin filaments. PKA
phosphorylates Alpha adducin and Beta
adducin and reduces their affinity for Fodrin
(spectrin)/Actin complexes as well as the
activity of Adducins in promoting binding of
Fodrin (spectrin) to Actin
filaments [6].
PKA directly phosphorylates monomeric
Actin, which causes a significant decrease in monomer
'polymerizibility'.
Myosin-based contractility is important for several aspects of cell
movement, including retraction of the trailing edge and less well-defined functions
within the leading edge, where Myosin light chain (MELC)
interaction with Actin and myosin-dependent contractility
are positively regulated by phosphorylation. MELC
phosphorylation is proximally controlled by the ratio of Myosin light chain kinase
(MLCK) and Protein phosphatase 1 catalytic subunit beta
isoform (MLCP) activities. The regulation of
MLCK and MLCP is intensely
complex, and involves cAMP-dependent
PKA signaling. MLCK is
activated by the
Ca(2+)/Calmodulin binding.
PKA can regulate Ca(2+) release
through phosphorylation and inhibition of Phospholipase C
(PLC-beta), resulting in the inactivation of receptors for
Inositol trisphosphate (IP3).
cAMP and PKA can up-regulate
MLCP activity through the Rho-associated, coiled-coil
containing protein kinase (ROCK)-dependent inhibition of
MLCP phosphorylation and inhibition of Ras homolog gene
family, member A (RhoA). The influence of
PKA on MLCK and
MLCP has the same effect on decreasing
MELC phosphorylation and stress fibers formation [2].
A kinase (PRKA) anchor protein 13 (LBC)
activity can be inhibited by the anchoring both PKA and
Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta polypeptide
(14-3-3 beta/alpha) proteins.
LBC has a close functional link with the
actin cytoskeleton through its interaction with the
RhoA and ability to promote G-protein coupled
receptors-dependent stress fiber formation.
Conversely, elevation of cAMP level and
activation of PKA have been shown to be required for
efficient cell migration, or hallmark steps of migration, in several systems as well.
These include: formation of filopodia and lamellipodia, which are governed by the
activation of Cell division cycle 42 (CDC42) and Ras-related
C3 botulinum toxin substrate 1 (Rac1)
respectively. Stimulation of PKA by
cAMP results in Rho guanine nucleotide exchange factor 7
(BETA-PIX) phosphorylation, which in turn controls
BETA-PIX translocation to focal complexes and
Rac1 and CDC42 activation
[7].
References:
- Defer N, Best-Belpomme M, Hanoune J
Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase.
American journal of physiology. Renal physiology 2000 Sep;279(3):F400-16
- Howe AK
Regulation of actin-based cell migration by cAMP/PKA.
Biochimica et biophysica acta 2004 Jul 5;1692(2-3):159-74
- Han J, Rose DM, Woodside DG, Goldfinger LE, Ginsberg MH
Integrin alpha 4 beta 1-dependent T cell migration requires both phosphorylation and dephosphorylation of the alpha 4 cytoplasmic domain to regulate the reversible binding of paxillin.
The Journal of biological chemistry 2003 Sep 12;278(37):34845-53
- Lebrand C, Dent EW, Strasser GA, Lanier LM, Krause M, Svitkina TM, Borisy GG, Gertler FB
Critical role of Ena/VASP proteins for filopodia formation in neurons and in function downstream of netrin-1.
Neuron 2004 Apr 8;42(1):37-49
- Keicher C, Gambaryan S, Schulze E, Marcus K, Meyer HE, Butt E
Phosphorylation of mouse LASP-1 on threonine 156 by cAMP- and cGMP-dependent protein kinase.
Biochemical and biophysical research communications 2004 Nov 5;324(1):308-16
- Matsuoka Y, Hughes CA, Bennett V
Adducin regulation. Definition of the calmodulin-binding domain and sites of phosphorylation by protein kinases A and C.
The Journal of biological chemistry 1996 Oct 11;271(41):25157-66
- Chahdi A, Miller B, Sorokin A
Endothelin 1 induces beta 1Pix translocation and Cdc42 activation via protein kinase A-dependent pathway.
The Journal of biological chemistry 2005 Jan 7;280(1):578-84
