estion 3 (1pt). Cancer cells have been shown to respond to high levels of EGF (e
ID: 132031 • Letter: E
Question
estion 3 (1pt). Cancer cells have been shown to respond to high levels of EGF (epidermal growth factor, a signaling molecule that can tell cells to divide) by increasing their motility (metastasis). In 2009 DesMarais, et al found that metastatic breast cancer cells migrated more ready in the presence of EGF. The increased ???? migration was due to upregulation of ARP2/3! a. What is the normal function of ARP2/3 in the cell (check Wikipedia, which of the activities at right does ARP2/3 do?)? Rubric (0.2): correct function for ARP23 b. If ARP2/3 is active, what is the net result on the dynamics of actin microfilaments? Make sure to discuss the presence of actin-ATP and actin-ADP on the ends of microfilaments. Rubrie (0.2): Statement includes whether microfiaments are growing or shrinking (0.1) and the status of actin (ATP or ADP) on the ends of the microfilament (0.1) C. Let's think about a normal mammary gland cell (cell in the breast that makes milk). Reread the introduction to this question! Why is it important for a NORMAL mammary cell to have low ARP2/3 activity? Rubric (0.1): Are mammary cells stationary or motile? d. In the figure below, Cose (y-axis) represents formation of a filopodia or lamellipodia and indicates that the cell is migrating toward the pipette (panel A, bottom right). What happened to filopodia formation in the presence of EGF when ARP2/3 was depleted in the cell (panel B)? Rubric (0.2): Correct statement explaining whether filopodia were formed or not e. The result below shows you what happens if ARP2/3 is at low levels. Now, explain why increased activity of ARP2/3 in the presence of EGF will increase cell migration. Rubric (0.3): Statement of effect of active ARP2/3 on microfilament dynamics (growthl'shrinkage) (0.15) Explanation why MF dynamics would increase cell migration (0.15). O.a control ARP2/3 Back Front 43 DepletedExplanation / Answer
a. ARP (Actin-related Protein) 2/3 is a protein complex made up of seven subunits. It helps in regulation of Actin dynamics. Two subunits ARP 2 and ARP 3 individually mimic the actin monomer and acts as nucleation site for the polymerization of new actin filament.
b. Activation of ARP 2/3 complex requires an activated form of Wiskott-Aldrich Syndrome protein (WASP). In activated state, both ARP 2 and ARP 3 are bound with ATP molecules. Binding with WASP increases the affinity of ARPs towards ATP. This ATP is hydrolyzed for initiation of Actin nucleation. Activation of ARP 2/3 leads to formation of a heterodimer analogous to actin filament and it forms the base for polymerization of new actin filament at the site. Actin-ATP is present at the start site.
c. Generally, normal epithelial cells are stationary. They grow in size but does not require high amount of motility. So, the normal mammary cells are having low expression of ARP 2/3 proteins. However, cancerous cells alter the integrin composition, thus signaling the cell to increase the expression of ARP 2/3 and start migration of cells.
d. Filopodia is cytoplasmic projection present on the surface of migrating cells. They are mainly polymerizing actin filaments. Filopodia binds with substratum and senses the environment through which migration of cell is occurring. Expression of EGF (Epidermal growth factor) is crucial for invasion and metastasis of tumor cells. But, in case of low expression of ARP 2/3, lamellipodia and filopodia expression is lowered drastically, thus down regulating the metastasis progression.
e. In case of increased activity of ARP 2/3, actin microfilament polymerization will be increased, that will increase the motility of migrating cells. Presence of EGF stimulates this process by down regulating other signaling pathways that may alter the assembly of ARP 2/3 heterodimer, making them inactive.
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