Clinical_Rounds_in_Endocrinology_Volume_II_-_Pediatric_Endocrinology

396

35. What is the molecular mechanism for the development of multiple neoplasias in
    patients with Carney’s complex?

Protein kinase A (PRKA) is an enzyme which is ubiquitously expressed and is

involved in cell growth and proliferation in cyclic AMP-responsive tissues. The

PRKA, a heterotetramer, consists of two regulatory (R) and two catalytic (C)

subunits. Stimulation of adenylyl cyclase through G protein-coupled receptor

(GPCR) activation leads to cAMP synthesis, which in turn results in dissocia-

tion of regulatory subunits from the catalytic subunits. The free catalytic sub-

units lead to activation of downstream pathway (e.g., cyclic AMP- responsive

element-binding protein 1, i.e., CREB) which promotes cell growth and prolif-

eration. PRKAR1A gene encodes the regulatory subunit of the PRKA enzyme,

and its mutation leads to structural defects in the regulatory subunits. The

defective regulatory subunits fail to bind with catalytic subunits, thereby unre-

strained catalytic subunit activity results in tumorigenesis in cAMP-responsive

tissues in patients with Carney’s complex. This is depicted in the figure given

below (Fig. 11.7).

Gβ

Gβ

Gγ

Gγ

Gα

GDP Gα

GTP

cAMP

Active PKA

Inactive PKA ATP

Plasma Membrane

RR

RR

C C

C C

Active

AC

Inactive

AC

Serine-threonine phosphorylation of substrates (CREB)

Fig. 11.7 Molecular mechanism of PRKA-mediated cell growth and proliferation

11 Multiple Endocrine Neoplasia