Cell Biology Lecture No. 21: Cell Signalling
Wednesday March 27 , 2013h
Signal Transduction & Its Players:
-Signal transduction is the conversion of one signal into another and it involves the external
stimulus of growth factors, cytokines, hormones, the ECM, neurotransmitters, light, sound, etc.
The field of signal transduction is incredibly broad as it covers all aspects of normal
development and physiology in cells. Understanding how signal transduction works can give us
insight as to how certain diseases such as cancer and heart disease are initiated. Important
players in signal transduction include: Receptor Tyrosine Kinases (RTKs), G-protein Coupled
Receptors, proto-oncogenes (e.g. Ras), and Mitogen Activated Protein Kinases (MAPKs).
Basic Elements Of Cell Signalling:
-No human cells live in isolation, which is why communication between cells is often mediated
mainly by extracellular signal molecules. All cells receive and respond to signals from their
environment. Signals or signalling molecules (referred to as ligands or primary messengers) are
an essential element of cell signalling pathways and can be: small molecules (e.g. organic
chemicals the body produces like epinephrine and acetylcholine, peptide hormones like insulin,
or monoamines that act like neurotransmitters) or large molecules (e.g. growth factors,
cytokines, etc.). Receptors (both cell-surface and intracellular) are another important component
of cell signalling as they transmit signals by interacting with other effector proteins (causing
them to change their function or activity) or second messengers (e.g. Ca , cAMP, cGMP, IP , 3
DAG, NO, etc.).
-During intracellular reception, a small signal molecule with hydrophobic properties reaches a
target cell with the help of a carrier protein. The signal molecule will then dissociate from the
carrier protein, cross the membrane and bind an intracellular receptor protein (in the cytoplasm
or nucleus) so the signal can be transmitted. During cell-surface reception, a large hydrophilic
signal molecule will bind a cell-surface receptor protein and the signal will be transmitted inside
the cell through a series of biochemical processes.
-Lipid-soluble hormones bind to intracellular receptors which constitute the nuclear-receptor
superfamily of transcription factors. Most of these hormones are steroid hormones which derive
from cholesterol and are synthesized by the adrenal glands. The proteins in this nuclear-
receptor superfamily have highly conserved DNA- and ligand-binding domains along with a
variable region for specificity. Some of the proteins in this superfamily are found in the
cytoplasm (estrogen receptor, progesterone receptor, glucocorticoid receptor), while others are
found in the nucleus (thyroxine receptor, retinoic acid receptor).
Gene Activation By A Nuclear Receptor: -The characteristic nucleotide sequences of the DNA sites that bind nuclear receptors are called
response elements. In the absence of the glucocorticoid hormone, the glucocorticoid receptor is
trapped in the cytoplasm by inhibitor proteins (e.g. HSP90) that bind to its ligand-binding
domain. The binding of the glucocorticoid hormone to a glucocorticoid receptor releases the
inhibitor protein, allowing the receptor to enter the nucleus. Once inside the nucleus, the
receptor binds to a response element of the target gene and stimulates the pre-initiation
complex assembly required for gene transcription (accomplished by the receptor’s activation
domain). Note that in order for the receptor to bind its response element in the nucleus (through
its DNA-binding domain) it must first dimerize with another glucocorticoid receptor.
Basic Concepts Of Signal Transduction:
-The primary messenger (extracellular signal molecule) will bind a specific cell-surface receptor
protein and this will initiate a cascade of different secondary messengers (intracellular signalling
proteins or molecules) to transmit that signal inside the cell. These secondary messengers will
interact with different types of effector proteins responsible for carrying out a specific
physiological change in the cell. E.g. metabolic enzyme bringing about altered metabolism,
gene regulatory protein giving rise to altered gene expression or a cytoskeletal protein altering
cell shape or movement.
Four Forms Of Intercellular Signalling:
-There are four basic forms when it comes to intercellular signalling: endocrine signalling
(signalling to distant cells), paracrine signalling (signalling to nearby cells), autocrine signalling
(a cell signalling itself) and signalling by plasma membrane-attached proteins. In endocrine
signalling, the signal molecules are synthesized and secreted by endocrine cells (signalling
cells) and transported through the circulatory system to target cells (the term hormone generally
refers to signalling molecules that mediate endocrine signalling). In paracrine signalling, the
signalling molecules released by a cell affect only those target cells in close proximity (e.g.
neurotransmitters). In autocrine signaling cells respond to substances that they themselves
release. In “cell-cell” signalling by plasma membrane-attached proteins, proteins attached to the
plasma membrane of one cell can interact directly with cell-surface receptors on adjacent cells.
Note that some signalling molecules such as epinephrine can act in both endocrine and
paracrine signalling, while other signalling molecules such as epidermal growth factor (EGF)
can act by cell-cell, autocrine or paracrine signalling.
Signalling By Cell-Sur