Signaling Processes

peptides or proteins. Insulin, neurotransmitters, and certain growth factors are considered these types of ligands. Some amino acids are considered these types of ligands.

SIGNALING PROCESSES

With intracellular ligands, there is no ongoing signaling because the ligand binds directly to the gene and activates it. When the receptor attaches to the cell membrane, a signaling process needs to happen to send the signal into the cell. There are several intracellular signal transduction pathways that connect the ligand-receptor complex to the interior cell signal.

It all starts with the ligand binding to the cell-surface receptor, which has an intracellular domain that changes its configuration in certain ways. Another signaling molecule can become activated as a result of the ligand binding. The reaction goes from upstream to downstream. The ligand itself is the most upstream and the reaction proceeds more downstream. There is amplification of the signal so that one ligand can activate many molecules downstream of it.

One thing that can happen is that a protein can by phosphorylated in order to cause it to be activated. This is the addition of a phosphate group to a protein, which can only happen to three amino acids: threonine, serine, and tyrosine. It takes a kinase enzyme in order to cause this phosphorylation to happen. Phosphorylation can either activate, inactivate, or cause the breakdown of a protein molecule. Phosphorylation is not a permanent thing because phosphatases can ultimately remove the phosphate group. Kinases require ATP energy to do their job but the same isn’t true of a phosphatase.

Growth factor signaling is an example of the phosphorylation pathway. One example of this is epidermal growth factor. It involves a series of kinases that phosphorylate different proteins. Epidermal growth factor has two receptors next to one another. These receptors act as kinases to each other’s intracellular tails.

RAF is a kinase in this system that activates MEK, which in turn phosphorylates and activates ERK proteins. The ERK proteins activate many different target molecules. This three-tiered pathway is called the MAPK pathway, which stands for mitogen-

activated protein kinase pathway. The pathway is involved in promoting cell division. If overactive, it can result in cancer.

Many signaling pathways involve second messengers, which are non-protein molecules that are a part of the pathway. Calcium can be a second messenger as can inositol phosphates and cyclic AMP. Calcium is a common second messenger. Its normal concentration in the cell is low but it can be stored in places like the endoplasmic reticulum.

Usually, when calcium is a second messenger, there are upstream events that open a ligand-gated calcium ion channel so that calcium ions can be increased in the cell. There are certain proteins that have binding sites for calcium so that they change their shape. When it happens, for example, in pancreatic cells, it signals these cells to release insulin. When it happens in muscle cells, it triggers the contraction of the muscle cells.

Cyclic AMP is another common second messenger. It is a small molecule that is ultimately made from ATP. There is an enzyme called adenylyl cyclase that makes ATP into cyclic AMP, which has one phosphate group that is linked to the sugar in a cyclic or ring shape. Cyclic AMP can activate protein kinase A or PKA, which is different in different types of cells. Cyclic AMP can be turned off by phosphodiesterase enzymes, which break the ring so it becomes AMP, which isn’t functional.

Certain phospholipids can act as chemical messengers. Phospholipids known as phosphatidyl inositols are phosphorylated and split in two, with both halves acting as second messengers. There is an enzyme called phospholipase C that cleaves phospholipids into two fragments called DAG and IP3, which act as second messengers. The precursor molecule is called PIP2, which stays in the plasma membrane. Phospholipase C is also located in the plasma membrane.

DAG can stay in the plasma membrane, where it activates protein kinase C, which can phosphorylate things. PIP3 enters the cytoplasm, where it binds to ligand-gated calcium channels in the endoplasmic reticulum, which continues the cascade of signaling in certain cells. PIP3 causes the endoplasmic reticulum to release calcium ions, which have another effect on the cell.